Document ID: FDA-2017-N-1142-0001
Agency: fda
Document Type: Rule
Title: Medical Devices: Clinical Chemistry and Clinical Toxicology Devices; Classification of the High Throughput Genomic Sequence Analyzer for Clinical Use
Posted Date: 2017-03-14T04:00Z

[Federal Register Volume 82, Number 48 (Tuesday, March 14, 2017)]
[Rules and Regulations]
[Pages 13551-13553]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2017-04941]

[[Page 13551]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 862

[Docket No. FDA-2017-N-1142]

Medical Devices; Clinical Chemistry and Clinical Toxicology 
Devices; Classification of the High Throughput Genomic Sequence 
Analyzer for Clinical Use

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA) is classifying the high 
throughput genomic sequence analyzer for clinical use into class II 
(special controls). The special controls that will apply to the device 
are identified in this order and will be part of the codified language 
for the classification of the high throughput genomic sequence analyzer 
for clinical use device. The Agency is classifying the device into 
class II (special controls) in order to provide a reasonable assurance 
of safety and effectiveness of the device.

DATES: This order is effective March 14, 2017. The classification was 
applicable on November 19, 2013.

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, 
steven.tjoe@fda.hhs.gov.

SUPPLEMENTARY INFORMATION: 

I. Background

    In accordance with section 513(f)(1) of the Federal Food, Drug, and 
Cosmetic Act (the FD&C Act) (21 U.S.C. 360c(f)(1)), devices that were 
not in commercial distribution before May 28, 1976 (the date of 
enactment of the Medical Device Amendments of 1976), generally referred 
to as postamendments devices, are classified automatically by statute 
into class III without any FDA rulemaking process. These devices remain 
in class III and require premarket approval unless and until the device 
is classified or reclassified into class I or II, or FDA issues an 
order finding the device to be substantially equivalent, in accordance 
with section 513(i) of the FD&C Act, to a predicate device that does 
not require premarket approval. The Agency determines whether new 
devices are substantially equivalent to predicate devices by means of 
premarket notification procedures in section 510(k) of the FD&C Act (21 
U.S.C. 360(k)) and part 807 (21 CFR part 807) of the regulations.
    Section 513(f)(2) of the FD&C Act, also known as De Novo 
classification, as amended by section 607 of the Food and Drug 
Administration Safety and Innovation Act (Pub. L. 112-144), provides 
two procedures by which a person may request FDA to classify a device 
under the criteria set forth in section 513(a)(1) of the FD&C Act. 
Under the first procedure, the person submits a premarket notification 
under section 510(k) of the FD&C Act for a device that has not 
previously been classified and, within 30 days of receiving an order 
classifying the device into class III under section 513(f)(1) of the 
FD&C Act, the person requests a classification under section 513(f)(2). 
Under the second procedure, rather than first submitting a premarket 
notification under section 510(k) of the FD&C Act and then a request 
for classification under the first procedure, the person determines 
that there is no legally marketed device upon which to base a 
determination of substantial equivalence and requests a classification 
under section 513(f)(2) of the FD&C Act. If the person submits a 
request to classify the device under this second procedure, FDA may 
decline to undertake the classification request if FDA identifies a 
legally marketed device that could provide a reasonable basis for 
review of substantial equivalence with the device or if FDA determines 
that the device submitted is not of ``low-moderate risk'' or that 
general controls would be inadequate to control the risks and special 
controls to mitigate the risks cannot be developed.
    In response to a request to classify a device under either 
procedure provided by section 513(f)(2) of the FD&C Act, FDA shall 
classify the device by written order within 120 days. This 
classification will be the initial classification of the device. In 
accordance with section 513(f)(1) of the FD&C Act, FDA issued an order 
on September 13, 2013, classifying the Illumina MiSeqDx Platform into 
class III, because it was not substantially equivalent to a device that 
was introduced or delivered for introduction into interstate commerce 
for commercial distribution before May 28, 1976, or a device which was 
subsequently reclassified into class I or class II.
    On September 23, 2013, FDA received from Illumina, Inc., a request 
for classification of the Illumina MiSeqDx Platform submitted under 
section 513(f)(2) of the FD&C Act. In accordance with section 513(f)(2) 
of the FD&C Act, FDA reviewed the request in order to classify the 
device under the criteria for classification set forth in section 
513(a)(1) of the FD&C Act. FDA classifies 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 to provide reasonable 
assurance of the safety and effectiveness of the device for its 
intended use. After review of the information submitted in the request, 
FDA determined that the device can be classified into class II with the 
establishment of special controls. FDA believes these special controls, 
in addition to general controls, will provide reasonable assurance of 
the safety and effectiveness of the device.
    Therefore, on November 19, 2013, FDA issued an order to the 
requestor classifying the device into class II. FDA is codifying the 
classification of the device by adding 21 CFR 862.2265.
    Following the effective date of this final classification order, 
any firm intending to market a high throughput genomic sequence 
analyzer for clinical use will need to comply with the special controls 
named in this final order. A De Novo classification decreases 
regulatory burdens. When FDA classifies a device type as class I or II 
via the De Novo pathway, other manufacturers do not have to submit a De 
Novo request or PMA in order to market the same type of device, unless 
the device has a new intended use or technological characteristics that 
raise different questions of safety or effectiveness. Instead, 
manufacturers can use the less burdensome pathway of 510(k), when 
necessary, to market their device, and the device that was the subject 
of the original De Novo classification can serve as a predicate device 
for additional 510(k)s from other manufacturers.
    The device is assigned the generic name high throughput genomic 
sequence analyzer for clinical use, and it is identified as an 
analytical instrument system intended to generate, measure and sort 
signals in order to analyze nucleic acid sequences in a clinical 
sample. The device may include a signal reader unit; reagent handling, 
dedicated instrument control, and other hardware components; raw data 
storage mechanisms; data acquisition software; and software to process 
detected signals.
    FDA has identified the following risks to health associated 
specifically with this type of device and the measures required to 
mitigate these risks:

[[Page 13552]]

   Table 1--High Throughput Genomic Sequence Analyzer for Clinical Use
                      Risks and Mitigation Measures
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         Identified risks to health              Required mitigations
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Inaccurate test results due to               Special Control (1) (21 CFR
 unavailability of necessary components of    862.2265(b)(1)).
 the instrument system.
Inaccurate results due to unknown            Special Control (2) (21 CFR
 performance of the instrument system.        862.2265(b)(2)).
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    FDA believes that the special controls, in combination with the 
general controls, address these risks to health and provide reasonable 
assurance of the safety and effectiveness. The special controls for a 
high throughput genomic sequence analyzer for clinical use include a 
detailed outline of analytical performance information that must be 
generated for the instrument system (i.e., platform and all associated 
software). This includes analytical validation using well characterized 
samples (i.e., well characterized or reference materials) to 
demonstrate the system's capabilities and to identify limitations.
    The validation testing, as required by the special controls, only 
establishes the instrument's general capabilities and does not 
establish the instrument's capabilities or suitability with respect to 
any specific claims. Instruments indicated for a specific diagnostic 
test, including those that make claims for a specific test, (e.g., 
hematology panel; oncology panel) require additional independent 
validation and are not high throughput genomic sequence analyzers for 
clinical use under 21 CFR 862.2265.
    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), if FDA determines that premarket notification is not necessary 
to provide reasonable assurance of the safety and effectiveness of the 
device. For this type of device, FDA believes premarket notification is 
not necessary to provide reasonable assurance of the safety and 
effectiveness of the device type and, therefore, is planning to exempt 
the device from the premarket notification requirements under section 
510(m) of the FD&C Act. Once finalized, persons who intend to market 
this device type need not submit a 510(k) premarket notification 
containing information on the high throughput genomic sequence analyzer 
for clinical use prior to marketing the device.

II. Analysis of Environmental Impact

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

III. Paperwork Reduction Act of 1995

    This final 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 862

    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 
862 is amended as follows:

PART 862--CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES

0
1. The authority citation for part 862 is revised to read as follows:

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

0
2. Add Sec.  862.2265 to subpart C to read as follows:

Sec.  862.2265  High throughput genomic sequence analyzer for clinical 
use.

    (a) Identification. A high throughput genomic sequence analyzer for 
clinical use is an analytical instrument system intended to generate, 
measure and sort signals in order to analyze nucleic acid sequences in 
a clinical sample. The device may include a signal reader unit; reagent 
handling, dedicated instrument control, and other hardware components; 
raw data storage mechanisms; data acquisition software; and software to 
process detected signals.
    (b) Classification. Class II (special controls). The special 
controls for this device are:
    (1) The labeling for the instrument system must reference legally 
marketed pre-analytical and analytical reagents to be used with the 
instrument system and include or reference legally marketed analytical 
software that includes sequence alignment and variant calling 
functions, to be used with the instrument system.
    (2) The labeling for the instrument system must include a 
description of the following information:
    (i) The specimen type(s) validated as an appropriate source of 
nucleic acid for this instrument.
    (ii) The type(s) of nucleic acids (e.g., germline DNA, tumor DNA) 
validated with this instrument.
    (iii) The type(s) of sequence variations (e.g. single nucleotide 
variants, insertions, deletions) validated with this instrument.
    (iv) The type(s) of sequencing (e.g., targeted sequencing) 
validated with this instrument.
    (v) The appropriate read depth for the sensitivity claimed and 
validation information supporting those claims.
    (vi) The nucleic acid extraction method(s) validated for use with 
the instrument system.
    (vii) Limitations must specify the types of sequence variations 
that the instrument cannot detect with the claimed accuracy and 
precision (e.g., insertions or deletions larger than a certain size, 
translocations).
    (viii) Performance characteristics of the instrument system must 
include:
    (A) Reproducibility data generated using multiple instruments and 
multiple operators, and at multiple sites. Samples tested must include 
all claimed specimen types, nucleic acid types, sequence variation 
types, and types of sequencing. Variants queried shall be located in 
varying sequence context (e.g., different chromosomes, GC-rich 
regions). Device results shall be compared to reference sequence data 
with high confidence.
    (B) Accuracy data for all claimed specimen types and nucleic acid 
types generated by testing a panel of well characterized samples to 
query all claimed sequence variation types, types of sequencing, and 
sequences located in varying sequence context (e.g., different 
chromosomes, GC-rich regions). The well-characterized sample panel 
shall include samples from at least two sources that have highly 
confident sequence based on well-validated sequencing methods. At least 
one

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reference source shall have sequence generated independently of the 
manufacturer with respect to technology and analysis. Percent agreement 
and percent disagreement with the reference sequences must be described 
for all regions queried by the instrument.
    (C) If applicable, data describing endogenous or exogenous 
substances that may interfere with the instrument system.
    (D) If applicable, data demonstrating the ability of the system to 
consistently generate an accurate result for a given sample across 
different indexing primer combinations.
    (ix) The upper and lower limit of input nucleic acid that will 
achieve the claimed accuracy and reproducibility. Data supporting such 
claims must also be summarized.

    Dated: March 8, 2017.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2017-04941 Filed 3-13-17; 8:45 am]
 BILLING CODE 4164-01-P