
[Federal Register Volume 77, Number 53 (Monday, March 19, 2012)]
[Proposed Rules]
[Pages 16126-16129]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-6518]



  Federal Register / Vol. 77, No. 53 / Monday, March 19, 2012 / 
Proposed Rules  

[[Page 16126]]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 866

[Docket No. FDA-2012-N-0159]


Microbiology Devices; Reclassification of Nucleic Acid-Based 
Systems for Mycobacterium tuberculosis Complex

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

-----------------------------------------------------------------------

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). These devices are intended to be used as an aid in the 
diagnosis of pulmonary tuberculosis.

DATES: Submit either electronic or written comments by June 18, 2012. 
See section IX of this document 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-2012-
N-0159, by any of the following methods:
    Electronic Submissions
    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
    Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     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-2012-N-0159 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, 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) (Pub. L. 
94-295), the Safe Medical Devices Act of 1990 (Pub. L. 101-629), and 
the Food and Drug Administration Modernization Act of 1997 (FDAMA) 
(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 (21 CFR part 807) of the regulations. Section 510(k) of the 
FD&C Act and the implementing regulation 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 the device is 
classified or reclassified into class I or class 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 and 
part 807 of FDA's regulations.
    Devices of a new type that FDA has not previously classified based 
on risk are ``automatically'' or ``statutorily'' classified into class 
III by operation of section 513(f)(1) of the FD&C Act, regardless of 
the level of risk they pose. This is because, by definition, a new type 
of device would not be within a type that was on the market before the 
1976 Medical Device Amendments or that has since been classified into 
class I or class II. Congress enacted section 513(f)(2) of the FD&C Act 
as part of FDAMA. The process created by this provision, which is 
referred to in FDAMA as the Evaluation of Automatic Class III 
Designation, will be referred to as the ``de novo process''. Congress 
included this section to limit unnecessary expenditure of FDA and 
industry resources that could occur if lower risk devices were subject 
to premarket approval under section 515 of the FD&C Act (21 U.S.C. 
360e).
    Reclassification of classified postamendment devices is governed by 
section 513(f)(3) of the FD&C Act. This section provides that FDA may 
initiate the reclassification of a device classified into class III 
based under section 513(e) of the FD&C Act. FDA's regulations in Sec.  
860.130 (21 CFR 860.130) set forth the procedures for the filing and 
review of a petition for reclassification of such class III devices. In 
order to change the

[[Page 16127]]

classification of the device, it is necessary that the proposed new 
class have sufficient regulatory controls to provide reasonable 
assurance of the safety and effectiveness of the device for its 
intended use.

II. Regulatory Background of the Device

    Nucleic acid-based in vitro diagnostic devices 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 
Sec.  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 Reclassification Decision

    At an FDA/Centers for Disease Control (CDC)/National Institute of 
Allergy and Infectious Diseases (NIAID) public workshop entitled 
``Advancing the Development of Diagnostic Tests and Biomarkers for 
Tuberculosis,'' held in Silver Spring, MD, on June 7 and 8, 2010 (Ref. 
1), 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. 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 (Microbiology Devices Panel) on June 29, 2011 (Ref. 
2). Although not a formal reclassification meeting, 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. The panel was not asked to vote on whether actual 
reclassification should occur or to assess whether any previously 
approved device or specific device currently under development 
warranted reclassification.
    All panel members expressed the opinion that sufficient data and 
information exists such that the risks of false positive and false 
negative results can be mitigated to allow a special controls guidance 
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. 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 (guidance document and limitations on 
the distribution) 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 healthcare workers handling specimens and control 
materials with the possibility of transmission of tuberculosis 
infection to healthcare 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 
guidance 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 guidance 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 healthcare workers handling specimens and 
control materials with the possibility of transmission of tuberculosis 
infection to healthcare workers could be addressed similarly to 
existing devices of this type that we have already approved. It is

[[Page 16128]]

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 guidance 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 Panel 
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 management or 
[tuberculosis] control activities'' (Ref. 3).

VIII. Special Controls

    FDA believes that, in addition to general controls, the proposed 
special controls discussed in this document are adequate to address the 
risks to health.
    FDA believes that the draft guidance document entitled ``Nucleic 
Acid-Based In Vitro Diagnostic Devices for the Detection of 
Mycobacterium tuberculosis Complex in Respiratory Specimens,'' will 
address the risks previously identified in this document and provide a 
reasonable assurance of safety and effectiveness of the device. The 
class II special controls guidance document provides information on how 
to meet premarket (510(k)) submission requirements for the device in 
sections that discuss analytical performance studies, performance 
studies using clinical specimens, and labeling. FDA believes that the 
class II special controls guidance document, which incorporates 
analytical studies, performance standards, and labeling statements and 
recommendations, minimizes risks to health and provides reasonable 
assurance of device safety and effectiveness.
    Elsewhere in this issue of the Federal Register, FDA is publishing 
a notice of availability of this class II special controls guidance 
document that the Agency intends to use for this device.

            Table 1--Risks to Health and Mitigation Measures
------------------------------------------------------------------------
       Identified risks             Recommended mitigation measures
------------------------------------------------------------------------
False positive test results    Device Description
 may lead to incorrect         Performance Studies
 treatment of the individual   Labeling.
 with possible adverse
 effects. The patient may be
 subjected to unnecessary
 isolation and/or other human
 contact limitations.
 Unnecessary contact
 investigations may also
 occur.
False negative test results    Device Description
 could result in disease       Performance Studies
 progression and the risk of   Labeling.
 transmitting disease to
 others.
Biosafety risks to healthcare  Labeling.
 workers handling specimens
 and control materials with
 the possibility of
 transmission of tuberculosis
 infection to healthcare
 workers.
------------------------------------------------------------------------

IX. Proposed Effective Date

    FDA proposes that any final rule based on this proposal become 
effective 30 days after its date of publication in the Federal 
Register.

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. 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 
significant regulatory action as defined by the 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 rule would create no new 
burdens, the Agency proposes to certify that the final rule 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 $136

[[Page 16129]]

million, using the most current (2010) Implicit Price Deflator for the 
Gross Domestic Product. FDA does not expect this proposed rule to 
result in any 1-year expenditure that would meet or exceed this amount.
    Our estimate of benefits annualized over 20 years is $9.4 million 
at a 3-percent discount rate and $7.4 million at a 7-percent discount 
rate. The change in pre and postmarketing 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 (Ref. 4) is available in 
docket FDA-2012-N-0159 and at http://www.regulations.gov.

XII. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires Agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' Federal law includes an express preemption 
provision that preempts certain state requirements ``different from or 
in addition to'' certain Federal requirements applicable to devices. 
(See section 521 of the FD&C Act (21 U.S.C. 360k); Medtronic, Inc. v. 
Lohr, 518 U.S. 470 (1996); and Riegel v. Medtronic, Inc. 128 S. Ct. 999 
(2008)). If this proposed rule is made final, the special controls 
established by the final rule would create ``requirements'' for 
specific medical devices under 21 U.S.C. 360(k), even though product 
sponsors have some flexibility in how they meet those requirements (Cf. 
Papike v. Tambrands, Inc., 107 F.3d 737, 740-742 (9th Cir. 1997)).

XIII. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed rule contains no new 
collections of information. Therefore, clearance by the Office of 
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 
(the PRA) is not required.
    This proposed rule designates a draft guidance document as a 
special control. FDA also tentatively concludes that the draft special 
control guidance document does not contain new information collection 
provisions that are subject to review and clearance by OMB under the 
PRA. Elsewhere in this issue of the Federal Register, FDA is publishing 
a notice announcing the availability of that draft guidance document 
entitled ``Class II Special Controls Guidance Document: Nucleic Acid-
Based In Vitro Diagnostic Devices for the Detection of Mycobacterium 
tuberculosis Complex in Respiratory Specimens,'' which contains an 
analysis of the paperwork burden for the draft guidance.

XIV. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) either electronic or written comments regarding this 
document. 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.

XV. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but FDA is 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(1), 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 
Initial Regulatory Flexibility Analysis Unfunded Mandates Reform Act 
Analysis.

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 be amended as follows:

PART 866--IMMUNOLOGY AND MICROBIOLOGY DEVICES

    1. The authority citation for part 866 continues to read as 
follows:

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

    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 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.
    (b) Classification. Class II (special controls). The special 
control for this device is the FDA document entitled ``Class II Special 
Controls Guidance Document: Nucleic Acid-Based In Vitro Diagnostic 
Devices for the Detection of Mycobacterium tuberculosis Complex in 
Respiratory Specimens.'' For availability of the guidance document, see 
Sec.  866.1(e).

    Dated: March 13, 2012.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2012-6518 Filed 3-16-12; 8:45 am]
BILLING CODE 4160-01-P


