[Federal Register Volume 78, Number 118 (Wednesday, June 19, 2013)]
[Proposed Rules]
[Pages 36698-36702]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2013-14552]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 866
[Docket No. FDA-2013-N-0544]
Microbiology Devices; Reclassification of Nucleic Acid-Based
Systems for Mycobacterium tuberculosis Complex in Respiratory Specimens
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to
reclassify nucleic acid-based in vitro diagnostic devices for the
detection of Mycobacterium tuberculosis complex in respiratory
specimens from class III (premarket approval) into class II (special
controls). FDA is also issuing the draft special controls guideline
entitled ``Class II Special Controls Guideline: Nucleic Acid-Based In
Vitro Diagnostic Devices for the Detection of Mycobacterium
tuberculosis Complex in Respiratory Specimens.'' These devices are
intended to be used as an aid in the diagnosis of pulmonary
tuberculosis.
DATES: Submit either electronic or written comments on the proposed
rule by August 19, 2013. See section XIII for the proposed effective
date of any final rule that may publish based on this proposal.
ADDRESSES: You may submit comments, identified by Docket No. FDA-2013-
N-0544, by any of the following methods:
Electronic Submissions
Submit electronic comments in the following way:
[[Page 36699]]
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. FDA-2013-N-0544 for this rulemaking. All comments
received may be posted without change to http://www.regulations.gov,
including any personal information provided. For additional information
on submitting comments, see the ``Comments'' heading of the
SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket number(s), found in brackets in the heading of this document,
into the ``Search'' box and follow the prompts and/or go to the
Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville,
MD 20852.
FOR FURTHER INFORMATION CONTACT: Janice A. 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. Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended
by the Medical Device Amendments of 1976 (the 1976 amendments) (Public
Law 94-295), the Safe Medical Devices Act of 1990 (Pub. L. 101-629),
and the Food and Drug Administration Modernization Act of 1997 (Pub. L.
105-115), the Medical Device User Fee and Modernization Act of 2002
(Pub. L. 107-250), the Medical Devices Technical Corrections Act (Pub.
L. 108-214), and the Food and Drug Administration Amendments Act of
2007 (Pub. L. 110-85), establish a comprehensive system for the
regulation of medical devices intended for human use. Section 513 of
the FD&C Act (21 U.S.C. 360c) established three categories (classes) of
devices, reflecting the regulatory controls needed to provide
reasonable assurance of their safety and effectiveness. The three
categories of devices are class I (general controls), class II (special
controls), and class III (premarket approval).
Under the FD&C Act, FDA clears or approves the three classes of
medical devices for commercial distribution in the United States
through three regulatory processes: Premarket approval (PMA), product
development protocol, and premarket notification (a premarket
notification is generally referred to as a ``510(k)'' after the section
of the FD&C Act where the requirement is found). The purpose of a
premarket notification is to demonstrate that the new device is
substantially equivalent to a legally marketed predicate device. Under
section 513(i) of the FD&C Act, a device is substantially equivalent if
it has the same intended use and technological characteristics as a
predicate device, or has different technological characteristics but
data demonstrate that the new device is as safe and effective as the
predicate device and does not raise different issues of safety or
effectiveness.
FDA determines whether new devices are substantially equivalent to
previously offered 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 of the regulations (21 CFR part 807). Section 510(k) of the
FD&C Act and the implementing regulations in part 807, subpart E,
require a person who intends to market a medical device to submit a
premarket notification submission to FDA before proposing to begin the
introduction, or delivery for introduction into interstate commerce,
for commercial distribution of a device intended for human use.
In accordance with section 513(f)(1) of the FD&C Act, devices that
were not in commercial distribution before May 28, 1976, the date of
enactment of the 1976 amendments, generally referred to as
postamendment 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 FDA classifies the
device into class I or class II by issuing 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 or the device is reclassified into class I or class II. 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 and part 807 of FDA's regulations.
Section 513(f)(2) of the FD&C Act establishes procedures for ``de
novo'' risk-based review and classification of postamendment devices
automatically classified into class III by section 513(f)(1). Under
these procedures, any person whose device is automatically classified
into class III by section 513(f)(1) of the FD&C Act may seek
reclassification into class I or II, either after receipt of an order
finding the device to be not substantially equivalent, in accordance
with section 513(i) of the FD&C Act, to a predicate device that does
not require premarket approval, or at any time after determining there
is no legally marketed device upon which to base a determination of
substantial equivalence. In addition, under section 513(f)(3) of the
FD&C Act, FDA may initiate, or the manufacturer or importer of a device
may petition for, the reclassification of a device classified into
class III under section 513(f)(1).
II. Regulatory Background of the Device
A nucleic acid-based in vitro diagnostic device for the detection
of M. tuberculosis complex in respiratory specimens is a postamendment
device classified into class III under section 513(f)(1) of the FD&C
Act in 1995. Consistent with the FD&C Act and FDA's regulations in 21
CFR 860.130(a), FDA believes that these devices should be reclassified
from class III into class II because there is sufficient information
from FDA's accumulated experience with these devices to establish
special controls that can provide reasonable assurance of the device's
safety and effectiveness.
III. Identification
Nucleic acid-based in vitro diagnostic devices for the detection of
M. tuberculosis complex in respiratory specimens are qualitative
nucleic acid-based in vitro diagnostic devices intended to detect M.
tuberculosis complex nucleic acids extracted from human respiratory
specimens. These devices are non-multiplexed and intended to be used as
an aid in the diagnosis of pulmonary tuberculosis when used in
conjunction with clinical and other laboratory findings. These devices
do not include devices intended to detect the presence of organism
mutations associated with drug resistance. Respiratory specimens may
include sputum (induced or expectorated), bronchial specimens (e.g.,
bronchoalveolar lavage or bronchial aspirate), or tracheal aspirates.
IV. Background for Proposed Reclassification Decision
At an FDA/Centers for Disease Control (CDC)/National Institute of
Allergy and Infectious Diseases public
[[Page 36700]]
workshop entitled ``Advancing the Development of Diagnostic Tests and
Biomarkers for Tuberculosis'', held in Silver Spring, MD, on June 7 and
8, 2010, the class III designation for nucleic acid-based in vitro
diagnostic devices for the detection of M. tuberculosis complex in
respiratory specimens was raised as a barrier to advancing M.
tuberculosis diagnostics (Ref. 1). Based on discussion at the public
workshop, FDA agreed to consider this issue further and subsequently
convened a meeting of the Microbiology Devices Panel of the Medical
Devices Advisory Committee on June 29, 2011. Panel members were asked
to discuss if sufficient risk mitigation was possible for FDA to
initiate the reclassification process from class III to class II
devices for this intended use through the drafting of a special
controls guidance. All panel members expressed the opinion that
sufficient data and information exist such that the risks of false
positive and false negative results can be mitigated to allow a special
controls guideline to be created that would support reclassification
from class III to class II for nucleic acid-based in vitro diagnostic
devices for the detection of M. tuberculosis complex in respiratory
specimens (Ref. 2). All outside speakers at the open public hearing
session during the meeting also spoke in favor of reclassification.
V. Classification Recommendation
FDA is proposing that nucleic acid-based in vitro diagnostic
devices for the detection of M. tuberculosis complex in respiratory
specimens be reclassified from class III to class II. FDA believes that
class II with special controls (guideline document) would provide
reasonable assurance of the safety and effectiveness of the device.
Section 510(m) of the FD&C Act provides that a class II device may be
exempt from the premarket notification requirements under section
510(k), if the Agency determines that premarket notification is not
necessary to provide reasonable assurance of the safety and
effectiveness of the device. For this device, FDA believes that
premarket notification is necessary to provide reasonable assurance of
safety and effectiveness and, therefore, does not intend to exempt the
device from the premarket notification requirements.
VI. Risks to Health
After considering the information discussed by the Microbiology
Devices Panel during the June 29, 2011, meeting, the published
literature, and the Medical Device Reporting system reports, FDA
believes the following risks are associated with nucleic acid-based in
vitro diagnostic devices for the detection of M. tuberculosis complex
in respiratory specimens: (1) False positive test results may lead to
incorrect treatment of the individual with possible adverse effects.
The patient may be subjected to unnecessary isolation and/or other
human contact limitations. Unnecessary contact investigations may also
occur; (2) False negative test results could result in disease
progression and the risk of transmitting disease to others; and (3)
Biosafety risks to health care workers handling specimens and control
materials with the possibility of transmission of tuberculosis
infection to health care workers.
VII. Summary of the Reasons for Reclassification
FDA, consistent with the opinions expressed by the Microbiology
Devices Panel of the Medical Devices Advisory Committee, believes that
the establishment of special controls, in addition to general controls,
provides reasonable assurance of the safety and effectiveness of
nucleic acid-based in vitro diagnostic devices for the detection of M.
tuberculosis complex in respiratory specimens.
1. The safety and effectiveness of nucleic acid-based systems for
M. tuberculosis complex have become well-established since approval of
the first device for this use in 1995.
2. The risk of false positive test results can be mitigated by
specifying minimum performance standards in the special controls
guideline and including information regarding patient populations
appropriate for testing in the device labeling. Additional risk
mitigation strategies include the indication for use that the device be
used as an aid to the diagnosis of pulmonary tuberculosis in
conjunction with other clinical and laboratory findings. The device
also should be accurately described and have labeling that addresses
issues specific to these types of devices.
3. The risk of false negative test results can be mitigated by
specifying minimum performance standards for test sensitivity in the
special controls guideline and ensuring that different patient
populations are included in clinical trials. Additional risk mitigation
strategies include the indication for use that the device be used as an
aid to the diagnosis of pulmonary tuberculosis in conjunction with
other clinical and laboratory findings. The device also should be
accurately described and have appropriate labeling that addresses
issues specific to these types of devices.
4. Biosafety risks to health care workers handling specimens and
control materials with the possibility of transmission of tuberculosis
infection to health care workers could be addressed similarly to
existing devices of this type that we have already approved. It is
believed there are no additional biosafety risks introduced by
reclassification from class III to class II. The need for appropriate
biosafety measures can be addressed in labeling recommendations that
are included in the special controls guideline and by adherence to
recognized laboratory biosafety procedures.
Based on FDA's review of published literature, the information
presented by outside speakers invited to the Microbiology Devices
meeting, and the opinions of panel members expressed at that meeting,
FDA believes that there is a reasonable basis to determine that nucleic
acid-based in vitro diagnostic devices for the detection of M.
tuberculosis complex in respiratory specimens can provide the
significant benefit of rapid detection of infection in patients with
suspected tuberculosis as compared to traditional means of diagnosis.
For patients with acid-fast smear negative tuberculosis, nucleic acid-
based in vitro diagnostic devices for the detection of M. tuberculosis
complex in respiratory specimens are currently the only laboratory
tests available for rapid detection of active pulmonary tuberculosis.
Rapid identification of patients with active tuberculosis may have
significant benefits to the infected patient by earlier diagnosis and
management as well as potentially significant effects on the public
health by limiting disease spread.
Nucleic acid-based in vitro diagnostic devices for the detection of
M. tuberculosis complex in respiratory specimens have been approved for
marketing by FDA for over 15 years. There is substantial scientific and
medical information available regarding the nature, complexity, and
problems associated with these devices. Revised public health
recommendations for use, published by CDC on January 16, 2009,
recommended the use of nucleic acid amplification testing in
conjunction with acid-fast microscopy and culture and specifically
states that ``Nucleic acid amplification testing should be performed on
at least one respiratory specimen from each patient with signs and
symptoms of pulmonary [tuberculosis] for whom a diagnosis of
[tuberculosis] is being considered but has not yet been established,
and for whom the test result would alter case
[[Page 36701]]
management or [tuberculosis] control activities'' (Ref 3).
VIII. Special Controls
FDA believes that the measures set forth in the special controls
guideline entitled ``Nucleic Acid-Based In Vitro Diagnostic Devices for
the Detection of Mycobacterium tuberculosis Complex in Respiratory
Specimens'' are necessary, in addition to general controls, to mitigate
the risks to health described in section VI in this document. As seen
in table 1, the special controls set forth in the guideline for this
device address each of the identified risks.
Table 1--Risks to Health and Mitigation Measures
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Recommended mitigation
Identified risks measures
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False positive test results may lead to Device Description.
incorrect treatment of the individual with Performance Studies.
possible adverse effects. The patient may be Labeling.
subjected to unnecessary isolation and/or other
human contact limitations. Unnecessary contact
investigations may also occur.
False negative test results could result in Device Description.
disease progression, and the risk of Performance Studies.
transmitting disease to others. Labeling.
Biosafety risks to health care workers handling Labeling.
specimens and control materials with the
possibility of transmission of tuberculosis
infection to health care workers.
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If this proposed rule is finalized, nucleic acid-based in vitro
diagnostic devices for the detection of M. tuberculosis complex in
respiratory specimens will be reclassified into class II. As discussed
in this document, the reclassification will be codified in 21 CFR
866.3372. Firms submitting a 510(k) for a nucleic acid-based in vitro
diagnostic devices for the detection of M. tuberculosis complex in
respiratory specimens will need either to: (1) Comply with the
particular mitigation measures set forth in the special controls
guideline or (2) use alternative mitigation measures, but demonstrate
to the Agency's satisfaction that alternative measures identified by
the firm will provide at least an equivalent assurance of safety and
effectiveness. Adherence to the criteria in the guideline, when
finalized, in addition to the general controls, is necessary to provide
a reasonable assurance of the safety and effectiveness of the devices.
IX. Electronic Access to the Special Controls Guideline
Persons interested in obtaining a copy of the draft guideline may
do so by using the Internet. A search capability for all Center for
Devices and Radiological Health guidelines and guidance documents is
available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm. The
guideline is also available at http://www.regulations.gov.
To receive ``Class II Special Controls Guideline: Nucleic Acid-
Based In Vitro Diagnostic Devices for the Detection of Mycobacterium
tuberculosis Complex in Respiratory Specimens,'' you may either send an
email request to [email protected] to receive an electronic copy of
the document or send a fax request to 301-847-8149 to receive a hard
copy. Please use the document number 1788 to identify the guideline you
are requesting.
X. Environmental Impact
The Agency has determined under 21 CFR 25.34(b) that this proposed
reclassification 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.
XI. Paperwork Reduction Act of 1995
This proposed rule refers to previously approved collections of
information found in 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 56.115 have been approved under
OMB control number 0910-0130; the collections of information in 21 CFR
part 807, subpart E have been approved under OMB control number 0910-
0120; the collections of information in 21 CFR part 812 have been
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.
XII. Clarifications to Special Controls Guidelines
This special controls guideline reflects changes the Agency is
making to clarify its position on the binding nature of special
controls. The changes include referring to the document as a
``guideline,'' as that term is used in section 513(a) of the FD&C Act,
which the Secretary has developed and disseminated to provide a
reasonable assurance of safety and effectiveness for class II devices,
and not a ``guidance,'' as that term is used in 21 CFR 10.115. The
guideline clarifies that firms will need either to: (1) Comply with the
particular mitigation measures set forth in the special controls
guideline or (2) use alternative mitigation measures, but demonstrate
to the Agency's satisfaction that those alternative measures identified
by the firm will provide at least an equivalent assurance of safety and
effectiveness. Finally, the guideline uses mandatory language to
emphasize that firms must comply with special controls to legally
market their class II devices. These revisions do not represent a
change in FDA's position about the binding effect of special controls,
but rather are intended to address any possible confusion or
misunderstanding.
XIII. Proposed Effective Date
FDA proposes that any final regulation based on this proposed rule
become effective 30 days after its date of publication in the Federal
Register.
XIV. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The Agency believes that this proposed rule is not a
[[Page 36702]]
significant regulatory action as defined by Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the proposed reclassification would relieve
manufacturers of premarket approval requirements of section 515 of the
FD&C Act (21 U.S.C. 360e) it would not create new burdens. Thus, the
Agency proposes to certify that the proposed rule, if finalized, will
not have a significant economic impact on a substantial number of small
entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $139 million, using the most current (2011) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule, if finalized, to result in any 1-year expenditure that
would meet or exceed this amount.
Our estimate of benefits annualized over 20 years is $11.85 million
at a 3 percent discount rate and $7.83 million at a 7 percent discount
rate. The change in pre- and post-marketing requirements between a
510(k) and a PMA lead to benefits in the form of reduced submission
costs, review-related activities, and inspections. Another
unquantifiable benefit from the rule is that a decrease in entry could
lead to further product innovation. FDA is unable to quantify the costs
that could arise if there is a change in risk which could lead to
adverse events, recalls, warning letters, or unlisted letters.
The full discussion of economic impacts is available in docket FDA-
2013-N-0544 at http://www.regulations.gov, and at http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/default.htm (Ref.
4).
XV. Comments
Interested persons may submit either electronic comments regarding
this document or the associated Special Controls guideline to http://www.regulations.gov or written comments to the Division of Dockets
Management (see ADDRESSES). It is only necessary to send one set of
comments. Identify comments with the docket number found in brackets in
the heading of this document. Received comments may be seen in the
Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday, and will be posted to the docket at http://www.regulations.gov.
XVI. References
The following references have been placed on display in the Dockets
Management Branch (see ADDRESSES) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday, and are available
electronically at http://www.regulations.gov. (FDA has verified all the
Web site addresses in this reference section, but we are not
responsible for any subsequent changes to the Web sites after this
document publishes in the Federal Register.)
1. Transcript of the Tuberculosis Public Workshop, June 7, 2010,
(Available at: http://www.fda.gov/downloads/ScienceResearch/SpecialTopics/CriticalPathInitiative/UpcomingEventsonCPI/UCM289182.doc, accessed on January 25, 2012.)
2. Transcript of FDA's Microbiology Devices Panel Meeting, June
29, 2011. (Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MicrobiologyDevicesPanel/UCM269469.pdf.)
3. ``Updated Guidelines for the Use of Nucleic Acid
Amplification Tests in the Diagnosis of Tuberculosis,'' Morbidity
and Mortality Weekly Report (MMWR), vol. 58, pp. 7-10, January 16,
2009. (Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5801a3.htm, accessed on July 26, 2011.)
4. Full Disclosure Preliminary Regulatory Impact Analysis of the
proposed rule ``Microbiology Devices; Reclassification of Nucleic
Acid-Based Systems for Mycobacterium tuberculosis Complex in
Respiratory Specimens,'' Docket No. FDA-2013-N-0544.
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, it is
proposed that 21 CFR part 866 is amended as follows:
PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES
0
1. The authority citation for part 866 continues to read as follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
0
2. Add Sec. 866.3372 to subpart D to read as follows:
Sec. 866.3372 Nucleic acid-based in vitro diagnostic devices for the
detection of Mycobacterium tuberculosis complex in respiratory
specimens.
(a) Identification. Nucleic acid-based in vitro diagnostic devices
for the detection of Mycobacterium tuberculosis complex in respiratory
specimens are qualitative nucleic acid-based in vitro diagnostic
devices intended to detect Mycobacterium tuberculosis complex nucleic
acids extracted from human respiratory specimens. These devices are
non-multiplexed and intended to be used as an aid in the diagnosis of
pulmonary tuberculosis when used in conjunction with clinical and other
laboratory findings. These devices do not include devices intended to
detect the presence of organism mutations associated with drug
resistance. Respiratory specimens may include sputum (induced or
expectorated), bronchial specimens (e.g., bronchoalveolar lavage or
bronchial aspirate), or tracheal aspirates.
(b) Classification. Class II (special controls). The special
control for this device is the FDA document entitled ``Class II Special
Controls Guideline: Nucleic Acid-Based In Vitro Diagnostic Devices for
the Detection of Mycobacterium tuberculosis Complex in Respiratory
Specimens.'' For availability of the guideline document, see Sec.
866.1(e).
Dated: June 12, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-14552 Filed 6-18-13; 8:45 am]
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