63034 Federal Register / Vol. 79, No. 204 / Wednesday, October 22, 2014 / Rules and Regulations 

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. 

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 MTBcomplex 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 ‘‘lowmoderate 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® 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 MTBcomplex antibiotic resistance in 

respiratory specimens, and it is 

identified as qualitative nucleic acidbased 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: 


tkelley on DSK3SPTVN1PROD with RULES
Federal Register / Vol. 79, No. 204 / Wednesday, October 22, 2014 / Rules and Regulations 63035 

TABLE 1—IDENTIFIED RISKS TO HEALTH AND MITIGATION MEASURES

Identified risks to health Mitigation measures 

False positive test results for the presence of MTB-complex may lead 

to incorrect treatment of the individual with possible adverse effects. 

The patient may be subjected to unnecessary isolation. Unnecessary 

contact investigations may also occur.

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 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 presence of MTB-complex could contribute to disease progression and increase the risk of transmitting infection to others.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 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 presence of genetic mutations associated with MTB-complex antibiotic resistance may lead to incorrect 

treatment of the individual with possible adverse effects. The patient 

may be subjected to unnecessary isolation. Unnecessary contact investigations may also occur.

§ 866.3373(b)(2) (21 CFR 866.3373(b)(2)), which addresses the mitigation of risks specific to the detection of the genetic mutations associated with antibiotic resistance of M. tuberculosis complex. 

False negative test results for the presence of genetic mutations associated with MTB-complex antibiotic resistance could contribute to disease progression and increase the risk of transmitting antibiotic resistant tuberculosis to others.§ 866.3373(b)(2), which addresses the mitigation of risks specific to the 

detection of the genetic mutations associated with antibiotic resistance of M. tuberculosis complex. 

Biosafety risks to health care workers handling specimens and control 

materials with the possibility of transmission of tuberculosis infection 

to health care workers.

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 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 § 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 MTBcomplex antibiotic resistance in 

respiratory specimens devices into class 

II. FDA is codifying this device type by 

adding § 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 MTBcomplex 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. 


tkelley on DSK3SPTVN1PROD with RULES
63036 Federal Register / Vol. 79, No. 204 / Wednesday, October 22, 2014 / Rules and Regulations 

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 

■ 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. 

■ 2. Section 866.3373 is added to 

subpart D to read as follows: 

§ 866.3373 Nucleic acid-based in vitro 

diagnostic devices for the detection of 

Mycobacterium tuberculosis complex (MTBcomplex) 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-complexassociated 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 MTBcomplex. For availability of the 

document, see § 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 antibioticresistance 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 MTBcomplex containing nucleic acid 

sequences associated with antibiotic 

resistance and primers amplifying 

human housekeeping genes (e.g., 

RNaseP, b-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 MTBcomplex. 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 MTBcomplex 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 MTBcomplex. 

(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 antibioticresistant 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 

DEPARTMENT OF COMMERCE 

United States Patent and Trademark 

Office 

37 CFR Parts 1, 2, 7, 11, 41, and 42 

[Docket No.: PTO–P–2014–0045] 

RIN 0651–AC98 

Renaming of Express Mail® to Priority 

Mail Express®

AGENCY: United States Patent and 

Trademark Office, Commerce. 

ACTION: Final rule. 

SUMMARY: The United States Patent and 

Trademark (Office) is revising the rules 

of practice to change the phrase Express 

Mail or EXPRESS MAIL® to Priority 

Mail Express® due to the United States 

Postal Service (USPS) renaming Express 

Mail® to Priority Mail Express® on July 

28, 2013, and to make other changes to 

conform the nomenclature used in the 


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