[Federal Register Volume 79, Number 204 (Wednesday, October 22, 2014)]
[Rules and Regulations]
[Pages 63034-63036]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-25049]
[[Page 63034]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2014-N-1440]
Medical Devices; Immunology and Microbiology Devices;
Classification of Nucleic Acid-Based Devices for the Detection of
Mycobacterium Tuberculosis Complex and the Genetic Mutations Associated
With Antibiotic Resistance
AGENCY: Food and Drug Administration, HHS.
ACTION: Final order.
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SUMMARY: The Food and Drug Administration (FDA) is classifying nucleic
acid-based in vitro diagnostic devices for the detection of
Mycobacterium tuberculosis complex (MTB-complex) and the genetic
mutations associated with MTB-complex antibiotic resistance in
respiratory specimens devices into class II (special controls). The
Agency is classifying the device into class II (special controls)
because special controls, in addition to general controls, will provide
a reasonable assurance of safety and effectiveness of the device.
DATES: This order is effective November 21, 2014. The classification
was applicable July 25, 2013.
FOR FURTHER INFORMATION CONTACT: Janice Washington, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 5554, Silver Spring, MD 20993-0002, 301-
796-6207.
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, 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 will
classify the device by written order within 120 days. This
classification will 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 announcing this
classification.
On June 13, 2013, Cepheid submitted a request for de novo
classification of the Xpert[supreg] MTB/RIF Assay 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 for de novo classification 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 will provide
reasonable assurance of the safety and effectiveness of the device.
The device is assigned the generic name nucleic acid-based in vitro
diagnostic devices for the detection of MTB-complex and the genetic
mutations associated with MTB-complex antibiotic resistance in
respiratory specimens, and it is identified as qualitative nucleic
acid-based devices that detect the presence of MTB-complex-associated
nucleic acid sequences in respiratory samples. These devices are
intended to aid in the diagnosis of pulmonary tuberculosis and the
selection of an initial treatment regimen when used in conjunction with
clinical findings and other laboratory results. These devices do not
provide confirmation of antibiotic susceptibility since other
mechanisms of resistance may exist that may be associated with a lack
of clinical response to treatment other than those detected by the
device.
FDA has identified the following risks to health associated with
this type of device and the measures required to mitigate these risks:
[[Page 63035]]
Table 1--Identified Risks to Health and Mitigation Measures
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Identified risks to health Mitigation measures
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False positive test results for the The FDA document entitled
presence of MTB-complex may lead to ``Class II Special Controls
incorrect treatment of the individual Guideline: Nucleic Acid-Based
with possible adverse effects. The In Vitro Diagnostic Devices
patient may be subjected to for the Detection of
unnecessary isolation. Unnecessary Mycobacterium tuberculosis
contact investigations may also occur. Complex and Genetic Mutations
Associated with Mycobacterium
tuberculosis Antibiotic
Resistance in Respiratory
Specimens,'' which addresses
this risk through:
Device Description Containing
the Information Specified in
the Special Control Guideline.
Performance Studies.
Labeling.
False negative test results for the The FDA document entitled
presence of MTB-complex could ``Class II Special Controls
contribute to disease progression and Guideline: Nucleic Acid-Based
increase the risk of transmitting In Vitro Diagnostic Devices
infection to others. for the Detection of
Mycobacterium tuberculosis
Complex and Genetic Mutations
Associated with Mycobacterium
tuberculosis Antibiotic
Resistance in Respiratory
Specimens,'' which addresses
this risk through:
Device Description Containing
the Information Specified in
the Special Control Guideline.
Performance Studies.
Labeling.
False positive test results for the Sec. 866.3373(b)(2) (21 CFR
presence of genetic mutations 866.3373(b)(2)), which
associated with MTB-complex antibiotic addresses the mitigation of
resistance may lead to incorrect risks specific to the
treatment of the individual with detection of the genetic
possible adverse effects. The patient mutations associated with
may be subjected to unnecessary antibiotic resistance of M.
isolation. Unnecessary contact tuberculosis complex.
investigations may also occur.
False negative test results for the Sec. 866.3373(b)(2), which
presence of genetic mutations addresses the mitigation of
associated with MTB-complex antibiotic risks specific to the
resistance could contribute to disease detection of the genetic
progression and increase the risk of mutations associated with
transmitting antibiotic resistant antibiotic resistance of M.
tuberculosis to others. tuberculosis complex.
Biosafety risks to health care workers The FDA document entitled
handling specimens and control ``Class II Special Controls
materials with the possibility of Guideline: Nucleic Acid-Based
transmission of tuberculosis infection In Vitro Diagnostic Devices
to health care workers. for the Detection of
Mycobacterium tuberculosis
Complex and Genetic Mutations
Associated with Mycobacterium
tuberculosis Antibiotic
Resistance in Respiratory
Specimens,'' which addresses
this risk through:
Labeling.
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FDA believes that the measures set forth in the special controls
guideline entitled ``Class II Special Controls Guideline: Nucleic Acid-
Based In Vitro Diagnostic Devices for the Detection of Mycobacterium
tuberculosis Complex and Genetic Mutations Associated with Antibiotic
Resistance in Respiratory Specimens'' and the special controls
identified in Sec. 866.3373(b)(2) of this order are necessary, in
addition to general controls, to mitigate the risks to health described
in table 1.
Therefore, on July 25, 2013, FDA issued an order to the petitioner
classifying nucleic acid-based in vitro diagnostic devices for the
detection of MTB-complex and the genetic mutations associated with MTB-
complex antibiotic resistance in respiratory specimens devices into
class II. FDA is codifying this device type by adding Sec. 866.3373.
II. 510(k) Premarket Notification
Following the effective date of this final classification order,
any firm submitting a 510(k) premarket notification for this device
type will need to comply with the special controls.
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. For this type of device, FDA has
determined that premarket notification is necessary to provide
reasonable assurance of the safety and effectiveness of the device.
Therefore, this type of device is not exempt from premarket
notification requirements. Persons who intend to market this type of
device must submit to FDA a premarket notification, prior to marketing
the device, which contains information about the nucleic acid-based in
vitro diagnostic devices for the detection of MTB-complex and the
genetic mutations associated with MTB-complex antibiotic resistance in
respiratory specimens they intend to market.
III. Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this action is
of 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 administrative 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 21 CFR parts 50 and 56 are approved under OMB control
number 0910-0755; 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 812 are approved under OMB control number 0910-0078; the
collections of information in 21 CFR part 820 have been approved under
OMB control number 0910-0073; and the collections of information in 21
CFR part 801 and 21 CFR 809.10 have been approved under OMB control
number 0910-0485.
[[Page 63036]]
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 21 CFR part 866 continues to read as
follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
0
2. Section 866.3373 is added to subpart D to read as follows:
Sec. 866.3373 Nucleic acid-based in vitro diagnostic devices for the
detection of Mycobacterium tuberculosis complex (MTB-complex) and the
genetic mutations associated with MTB-complex antibiotic resistance in
respiratory specimens.
(a) Identification. Nucleic acid-based in vitro diagnostic devices
for the detection of Mycobacterium tuberculosis complex (MTB-complex)
and the genetic mutations associated with MTB-complex antibiotic
resistance in respiratory specimens are qualitative nucleic acid-based
devices that detect the presence of MTB-complex-associated nucleic acid
sequences in respiratory samples. These devices are intended to aid in
the diagnosis of pulmonary tuberculosis and the selection of an initial
treatment regimen when used in conjunction with clinical findings and
other laboratory results. These devices do not provide confirmation of
antibiotic susceptibility since other mechanisms of resistance may
exist that may be associated with a lack of clinical response to
treatment other than those detected by the device.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) The FDA document entitled ``Class II Special Controls
Guideline: Nucleic Acid-Based In Vitro Diagnostic Devices for the
Detection of Mycobacterium tuberculosis Complex and Genetic Mutations
Associated with Antibiotic Resistance in Respiratory Specimens,'' which
addresses the mitigation of risks specific to the detection of MTB-
complex. For availability of the document, see Sec. 866.1(e).
(2) The following items, which address the mitigation of risks
specific to the detection of the genetic mutations associated with
antibiotic resistance of MTB-complex:
(i) The device must include an external positive assay control as
appropriate. Acceptable positive assay controls include MTB-complex
isolates containing one or more antibiotic-resistance associated target
sequences detected by the device.
(ii) The device must include internal controls as appropriate. An
acceptable internal control may include human nucleic acid co-extracted
with MTB-complex containing nucleic acid sequences associated with
antibiotic resistance and primers amplifying human housekeeping genes
(e.g., RNaseP, [beta]-actin).
(iii) The device's intended use must include a description of the
scope of antibiotic resistance targeted by the assay, i.e., the
specific drugs and/or drug classes.
(iv) The specific performance characteristics section of the
device's labeling must include information regarding the specificity of
the assay oligonucleotides for detecting mutations associated with
antibiotic resistance of MTB-complex, and any information indicating
the potential for non-specific binding (e.g., BLAST search).
(v) In demonstrating device performance you must perform:
(A) Pre-analytical studies that evaluate:
(1) Frozen samples. If there is use of any frozen samples in the
device performance studies, or if there is a device claim for the use
of frozen samples for testing, the effect of freezing samples prior to
testing and the effect of multiple freeze/thaw cycles on both
antibiotic susceptible and antibiotic resistant strains of MTB-complex.
(2) Nucleic acid extraction methods. Extraction methods must
parallel those used in devices for the detection of MTB-complex nucleic
acid and confirm that the detection of the genetic mutations associated
with antibiotic resistance is not affected.
(B) Analytical studies that analyze:
(1) Limit of Detection. Limit of Detection must be determined in
the most challenging matrix (e.g., sputum) claimed for use with the
device. The Limit of Detection must be determined using both antibiotic
susceptible and antibiotic resistant strains of MTB-complex. The
antibiotic resistant strains must be those with well characterized
genetic mutations associated with antibiotic resistance.
(2) Analytical Reactivity (Inclusivity). Testing must be conducted
to evaluate the ability of the device to detect genetic mutations
associated with antibiotic resistance in a diversity of MTB-complex
strains. Isolates used in testing must be well characterized. Isolate
strain characterization must be determined using standardized reference
methods recognized by a reputable scientific body and appropriate to
the strain lineage.
(3) Within-Laboratory (Repeatability) Precision Testing. Within-
laboratory precision studies, if appropriate, must include at least one
antibiotic resistant and one antibiotic susceptible strain of MTB-
complex.
(4) Between Laboratory Reproducibility Testing. The protocol for
the reproducibility study may vary slightly depending on the assay
format; however, the panel must include at least one antibiotic
resistant and one antibiotic susceptible strain of MTB-complex.
(C) Clinical Studies. Clinical performance of the device must be
established by conducting prospective clinical studies that include
subjects with culture confirmed active tuberculosis. Studies must
attempt to enroll subjects at risk for antibiotic-resistant MTB-
complex; however, it may be necessary to include supplemental
antibiotic resistant retrospective and contrived samples. Clinical
studies must compare device results to both phenotypic drug
susceptibility testing and genotypic reference methods. The genotypic
reference method must be a polymerase chain reaction based method that
uses primers different from those in the experimental device and
confirmed by bidirectional sequencing.
Dated: October 15, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-25049 Filed 10-21-14; 8:45 am]
BILLING CODE 4164-01-P