[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.
------------------------------------------------------------------------

    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