[Federal Register Volume 79, Number 178 (Monday, September 15, 2014)]
[Proposed Rules]
[Pages 54927-54936]
[FR Doc No: 2014-21814]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 870

[Docket No. FDA-2011-N-0650]

Cardiovascular Devices; Reclassification of External Pacemaker
Pulse Generator Devices; Reclassification of Pacing System Analyzers

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA) is proposing in this
administrative order to reclassify the external pacemaker pulse
generator (EPPG) devices, a preamendments class III device into class
II (special controls), and to amend the device identification and
reclassify the pacing system analyzers (PSAs) into class II (special
controls). Specifically, single and dual chamber PSAs, which are
currently classified with EPPG devices, and triple chamber PSAs
(TCPSAs), which are postamendments class III devices, are proposed to
be reclassified to class II devices. FDA is proposing this
reclassification based on new information pertaining to the device.
This proposed action would implement certain statutory requirements.

DATES: Submit either electronic or written comments on the proposed
order by December 15, 2014. See section XII for the effective date of
any final order that may publish based on this proposed order.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0650, 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:
     Mail/Hand delivery/Courier (for paper 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-2011-N-0650 for this order. 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: Hina Pinto, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, rm. 1652, Silver Spring, MD 20993,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The 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), 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 of 2004 (Public Law
108-214), the Food and Drug Administration Amendments Act of 2007 (Pub.
L. 110-85), and the Food and Drug Administration Safety and Innovation
Act (FDASIA) (Pub. L. 112-144) establishes 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).
    Section 513(a)(1) of the FD&C Act defines class II devices as those
devices for which the general controls by themselves are insufficient
to provide reasonable assurance of safety and effectiveness, but for
which there is sufficient information to establish special controls to
provide such assurance.
    Under section 513 of the FD&C Act, devices that were in commercial
distribution before the enactment of the 1976 amendments, May 28, 1976
(generally referred to as preamendments devices), are classified after
FDA has: (1) Received a recommendation from a device classification
panel (an FDA advisory committee); (2) published the panel's
recommendation for comment, along with a proposed regulation
classifying the device; and (3) published a final regulation
classifying the device. FDA has classified most preamendments devices
under these procedures.
    Devices that were not in commercial distribution prior to May 28,
1976 (generally referred to as postamendments devices), are
automatically classified by section 513(f) of the FD&C Act into class
III without any FDA rulemaking process. Those devices remain in class
III and require premarket approval unless, and until, the device is
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).
    A preamendments device that has been classified into class III and
devices found substantially equivalent by means of premarket
notification (510(k)) procedures to such a preamendments device or to a
device within that type may be marketed without submission of a
premarket approval (PMA) application until FDA issues a final order
under section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) requiring
premarket approval or until the device is subsequently reclassified
into class I or class II.
    On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA
amended the device reclassification procedures under section 513(e) of
the FD&C Act, changing the process for reclassifying a device from
rulemaking to an administrative order. Prior to the enactment of
FDASIA, FDA published a proposed rule under section 513(e) of the FD&C
Act proposing the reclassification of EPPG devices (76 FR 64223,
October 17, 2011). Three sets of comments were received on the proposed
rule. The three sets of comments submitted in response to the proposed
rule on EPPG devices will be considered under this proposed
administrative order and do not need to be resubmitted. FDA is issuing
this proposed administrative order to comply with the new procedural
requirement created by FDASIA when reclassifying a preamendments class
III device, as well as to reclassify a postamendments class III device.
Also, as required by section 513(e) of the FD&C Act for preamendment
devices, FDA convened a device classification panel meeting which
discussed the proposed reclassification on September 11, 2013 (78 FR
49272). This action is intended solely to fulfill the procedural
requirements for reclassification implemented by FDASIA.
    Section 513(e) of the FD&C Act provides that FDA may, by
administrative order, reclassify a device based upon ``new
information.'' FDA can initiate a reclassification under section 513(e)
or an interested person may petition FDA to reclassify a preamendments
device. The term ``new information,'' as used in section 513(e) of the
FD&C Act, includes information developed as a result of a reevaluation
of the data before the Agency when the device was originally
classified, as well as information not presented, not available, or not
developed at that time. (See, e.g., Holland-Rantos Co. v. United States
Dep't of Health, Educ., & Welfare, 587 F.2d 1173, 1174 n.1 (D.C. Cir.
1978); Upjohn v. Finch, 422 F.2d 944 (6th Cir. 1970); Bell v. Goddard,
366 F.2d 177 (7th Cir. 1966).)
    A postamendments device that has been initially classified in class
III under section 513(f)(1) of the FD&C Act may be reclassified later
into class I or class II under section 513(f)(3) of the FD&C Act.
Section 513(f)(3) provides that FDA acting by administrative order can
reclassify the device into class I or class II on its own initiative
under section 513(f)(1) of the FD&C Act, or in response to the petition
of the manufacturer or importer of the device. FDA's regulations in 21
CFR 860.134 set forth the procedures for the filing and review of a
petition for reclassification of these class III devices. To change the
classification of the device, the proposed new class must have
sufficient regulatory controls to provide reasonable assurance of the
safety and effectiveness of the device for its intended use.
    Reevaluation of the data previously before the Agency is an
appropriate

basis for subsequent regulatory action where the reevaluation is made
in light of newly available regulatory authority (see Bell v. Goddard,
supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762 F.Supp. 382, 388-391
(D.D.C. 1991)), or in light of changes in ``medical science.'' (See
Upjohn v. Flinch supra, 422 F.2d at 951.) Whether data before the
Agency are old or new data, the ``new information'' to support
reclassification under section 513(e) must be ``valid scientific
evidence,'' as defined in section 513(a)(3) of the FD&C Act and Sec.
860.7(c)(2). (See, e.g., General Medical Co. v. FDA, 770 F.2d 214 (D.C.
Cir. 1985); Contact Lens Manufacturers Association v. FDA, 766 F.2d 592
(D.C. Cir. 1985), cert. denied, 474 U.S. 1062 (1986).
    FDA relies upon ``valid scientific evidence'' in the classification
process to determine the level of regulation for devices. To be
considered in the reclassification process, the valid scientific
evidence upon which the Agency relies must be publicly available.
Publicly available information excludes trade secret and/or
confidential commercial information, e.g., the contents of a pending
premarket approval application (PMA). (See section 520(c) of the FD&C
Act (21 U.S.C. 360j(c)).
    Section 513(e)(1) of the FD&C Act sets forth the process for
issuing a final order. Specifically, prior to the issuance of a final
order reclassifying a device, the following must occur: (1) Publication
of a proposed order in the Federal Register; (2) a meeting of a device
classification panel described in section 513(b) of the FD&C Act; and
(3) consideration of comments from all affected stakeholders, including
patients, payors, and providers. In addition, the proposed order must
set forth the proposed reclassification, and a substantive summary of
the valid scientific evidence concerning the proposed reclassification,
including the public health benefits of the use of the device, and the
nature and incidence (if known) of the risk of the device. (See section
513(e)(1)(A)(i) of the FD&C Act.)
    Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the premarket notification requirements under section
510(k) of the FD&C Act if the Agency determines that premarket
notification is not necessary to assure the safety and effectiveness of
the device. FDA has determined that premarket notification is necessary
to reasonably assure the safety and effectiveness of EPPG and PSA
devices.

II. Regulatory History of the Device

A. EPPG Devices

    On March 9, 1979, FDA published a proposed rule in the Federal
Register for classification of EPPG devices into class III based on the
recommendation of the Cardiovascular Devices Panel (the Panel) (44 FR
13284 at 13372). The Panel meeting recommended EPPG devices be
classified into class III because the device provided temporary life
support and that certain kinds of failures could cause this device to
emit inappropriate electrical signals, which could cause cardiac
irregularities and death. The Panel indicated that general controls
alone would not be sufficient and that there was not enough information
to establish a performance standard. Consequently, the Panel believed
that premarket approval was necessary to reasonably assure the safety
and effectiveness of the device. In 1980, FDA classified EPPG into
class III under Sec.  870.3600 (21 CFR 870.3600) after receiving no
comments on the proposed rule (45 FR 7907, February 5, 1980). In 1987,
FDA published a clarification by inserting language in the codified
language stating that no effective date had been established for the
requirement for premarket approval for EPPG devices (52 FR 17732, May
11, 1987).
    In 2009, FDA published an order in the Federal Register under
section 515(i) of the FD&C Act to call for information on the remaining
class III 510(k) preamendment devices, including EPPG devices (74 FR
16214, April 9, 2009). In response to that order, FDA received two
reclassification petitions from one device manufacturer who requested
that EPPG devices be reclassified into class II. The manufacturers
stated that safety and effectiveness of these devices may be assured by
performance standards, the intended use environment, postmarket
surveillance to include Medical Device Reporting (MDRs), FDA
inspections of manufacturing facilities, and premarket review of
performance testing in a 510(k) submission. The manufacturers
specifically noted that the FDA recognized consensus standard,
International Electrotechnical Commission (IEC) 60601-2-31: 'Particular
requirements for the basic safety and essential performance of external
cardiac pacemakers with internal power source' provides adequate design
and testing parameters for EPPG devices.
    On October 17, 2011, FDA published a proposed rule proposing the
reclassification of EPPG devices from class III to class II (76 FR
64223) and announcing the availability of a draft Special Controls
Guidance Document that, if finalized, would serve as a special control,
if FDA reclassified these devices. FDA believed that the special
controls described in the draft special controls guidance document
entitled ``Class II Special Controls Guidance Document: External
Pacemaker Pulse Generator'' would be sufficient to mitigate the risks
to health associated with EPPG (Ref. 1).
    The proposed rule provided for a comment period that was open until
January 17, 2012. FDA received three sets of comments. These comments
stated that: (1) FDA should retain EPPG in class III, (2) FDA's
reclassification proposed rule was not adequately supported by new
publicly valid scientific evidence, (3) MDR data showed that existing
performance standards are insufficient, (4) there were no publicly
available performance standards that would apply to EPPG, (5) FDA
should convene an advisory committee (the Panel) to seek a
recommendation on the classification of EPPG, and (6) the recall
process after reclassification of EPPG would need to be clarified.
These comments were considered by FDA in drafting this proposed order.

B. PSA Devices

    Single and dual chamber PSAs have historically been classified with
EPPG devices. These devices combine the functionality of a single or
dual chamber EPPG, which is currently class III and the functionality
of a pacemaker electrode function tester, which is regulated as a class
II device (under Sec.  870.3720 (21 CFR 870.3720)). Single and dual
chamber PSA devices have been found substantially equivalent to EPPG
devices through the 510(k) process. Triple chamber PSA (TCPSA) devices
have not been determined to be substantially equivalent through the
510(k) process, and since this technology was not on the market in
1976, TCPSAs have been reviewed through the PMA process as
postamendment class III devices.
    On July 9, 2012, FDASIA was enacted, which amended the device
reclassification procedures under sections 513 and 515 of the FD&C Act.
Accordingly, FDA is issuing a proposed administrative order to comply
with the new procedural requirement created by FDASIA when
reclassifying a preamendments class III device. Further, FDA intends to
codify the proposed special controls within the Sec.  870.3600
classification regulation for EPPG and to create a separate

classification regulation for PSA devices.
    As explained further in section VII, a meeting of the Circulatory
System Devices Panel (the 2013 Panel) took place on September 11, 2013,
to discuss whether EPPG and TCPSA devices should be reclassified or
remain in class III (Ref. 2). FDA included a discussion of TCPSA
devices in the 2013 Panel discussion because the risks to health and
proposed special controls were very similar to those being proposed for
the EPPG devices already under consideration. The 2013 Panel
recommended that EPPG devices be reclassified to class II with special
controls when intended for cardiac rate control or prophylactic
arrhythmia prevention. The 2013 Panel also recommended that TCPSA
devices be reclassified to class II with special controls when intended
for use during the pulse generator implant procedure. FDA is not aware
of new information that would provide a basis for a different
recommendation or finding.

III. Device Description

A. EPPG Devices

    An EPPG is a device that has a power supply and electronic circuits
that produce a periodic electrical pulse to stimulate the heart. This
device, which is used outside the body, is used as a temporary
substitute for the heart's intrinsic pacing system until a permanent
pacemaker can be implanted, or to control irregular heartbeats in
patients following events such as cardiac surgery or a myocardial
infarction. The device may have adjustments for pacing rate, pulse
amplitude, pulse width (duration), R-wave sensitivity, and other pacing
variables.
    An EPPG device is designed to be used with cardiac pacing lead
systems for temporary atrial and/or ventricular pacing. An EPPG system
generally includes the pulse generator, extension cables, and adaptors
which connect the extension cable to the implanted pacing lead and are
critical to the functionality of the EPPG system. The pacing leads for
use with EPPG may be for temporary or permanent use for either
tranvenous or epicardial uses. The pacing leads are not considered part
of the EPPG device because they have their own regulatory designations
(21 CFR 870.3680) depending on their design and intended use.
    EPPG devices are used exclusively in hospital environments with the
patients supervised by qualified medical personnel. The electrical and
heart rhythm of patients are continuously monitored using EPPG-
independent electrocardiogram (ECG) monitors usually with alarm
functions. Independent ECG monitoring requirements are identified in
international standards, such as IEC 60601-2-31 for device design.
    FDA is also proposing in this order to slightly modify the
identification language from the way it is presently written in Sec.
870.3600(a) to clarify that these are prescription devices in
accordance with Sec.  801.109 (21 CFR 801.109).

B. PSA Devices

    A PSA combines the functionality of a pacemaker electrode function
tester (under Sec.  870.3720) and an EPPG. A pacemaker electrode
function tester is a device that is connected to an implanted pacemaker
lead that supplies an accurately calibrated, variable pacing pulse for
measuring the patient's pacing threshold and intracardiac R-wave
potential. A PSA can temporarily take over pacing functions while
simultaneously testing one or more implanted pacing leads. PSA devices
can be single, dual, or triple chamber, translating into the
measurement capabilities/functionalities of the device. Single chamber
PSAs typically measure pacing capture threshold, whereas in the case of
dual chamber PSAs, the device can also measure conduction times or
intrinsic atrioventricular delay. In the case of a TCPSA, the device
can also function as a biventricular external pacemaker and measure the
intrinsic intra-ventricular (VV) interval.

IV. Proposed Reclassification

A. EPPG Devices

    FDA is proposing that EPPG devices be reclassified from class III
to class II. In this proposed order, the Agency has identified special
controls under section 513(a)(1)(B) of the FD&C Act that, together with
general controls (including prescription-use restrictions) applicable
to the devices, would provide reasonable assurance of their safety and
effectiveness. Absent the special controls identified in this proposed
order, general controls applicable to the device are insufficient to
provide reasonable assurance of the safety and effectiveness of the
device. Since the time of the 1979 classification, new information
about use and pacing technology for this device has become sufficiently
available to establish special controls. FDA believes that this new
information is sufficient to demonstrate that the proposed special
controls, when finalized, can effectively mitigate the risks to health
identified in section V, and that these special controls, together with
general controls, will provide a reasonable assurance of safety and
effectiveness for EPPG devices.

B. PSA Devices

    FDA is proposing to create a separate classification regulation for
PSA devices, including single, dual, and triple chamber PSA devices
that will be reclassified from class III to class II. In this proposed
order, the Agency has identified special controls under section
513(a)(1)(B) of the FD&C Act that, together with general controls
(including prescription-use restrictions) applicable to the devices,
would provide reasonable assurance of their safety and effectiveness.
Absent the special controls identified in this proposed order, general
controls applicable to the device are insufficient to provide
reasonable assurance of the safety and effectiveness of the device.
Since the 1979 classification of temporary external pacing devices, new
information about device use and pacing technology has become available
to establish special controls. FDA believes that this new information
is sufficient to demonstrate that the proposed special controls can
effectively mitigate the risks to health identified in section V, and
that these special controls, together with general controls, will
provide a reasonable assurance of safety and effectiveness for PSA
devices.
    Section 510(m) of the FD&C Act authorizes the Agency to exempt
class II devices from premarket notification (510(k)) submission. FDA
has considered EPPG and PSA devices in accordance with the reserved
criteria set forth in section 513(a) and determined that both devices
require premarket notification (510(k) of the FD&C Act). Therefore, the
Agency does not intend to exempt these proposed class II devices from
premarket notification (510(k)) submission as provided under section
510(m) of the FD&C Act.

V. Risks to Health

A. EPPG Devices

    After considering available information for the classification of
these devices, including the recommendations of the advisory committees
(panels) for the classification of these devices, FDA has evaluated the
risks to health associated with the use of EPPG devices and determined
the following risks to health are associated with its use:
     Failure to pace: Improper settings, electromagnetic
interference, or failure

of mechanical/electrical components of the device can prevent pacing of
the patient's heart.
     Improperly high pacing rate: Undersensing during demand
pacing, unintended asynchronous pacing, or improper use of burst/
overdrive pacing can cause harmful acceleration of heart rate or induce
harmful arrhythmias such as ventricular tachycardia.
     Improperly low pacing rate: Oversensing or use error can
result in stimulation pulses being delivered at an unwanted low pacing
rate, which can result in untreated symptomatic bradycardia.
     Improper pacing leading to unwanted stimulation: Pacing
during vulnerable periods of the cardiac cycle or at higher than
programmed amplitude can induce arrhythmias.
     Micro/macro shock: Uncontrolled leakage currents or
patient auxiliary currents can cause an electric shock resulting in an
arrhythmia or cardiac tissue damage.

B. PSA Devices

    After considering available information for the classification of
these devices, including the recommendations of the advisory committees
(panels) for the classification of these devices, FDA has evaluated the
risks to health associated with the use of PSA devices and determined
the following risks to health are associated with its use:
     Failure to pace: Improper settings, electromagnetic
interference, or failure of mechanical/electrical components of the
device can prevent pacing of the patient's heart.
     Improperly high pacing rate: Undersensing during demand
pacing, unintended asynchronous pacing, or improper use of burst/
overdrive pacing can cause harmful acceleration of heart rate or induce
harmful arrhythmias such as ventricular tachycardia.
     Improperly low pacing rate: Oversensing or use error can
result in stimulation pulses being delivered at an unwanted low pacing
rate, which can result in untreated symptomatic bradycardia.
     Improper pacing leading to unwanted stimulation: Pacing
during vulnerable periods of the cardiac cycle or at higher than
programmed amplitude can induce arrhythmias. For TCPSAs, this risk
includes VV dyssynchrony.
     Micro/macro shock: Uncontrolled leakage currents or
patient auxiliary currents can cause an electric shock resulting in an
arrhythmia or cardiac tissue damage.
     Misdiagnosis: If the zero or calibration of the device is
inaccurate or unstable the device may generate inaccurate diagnostic
data. If inaccurate diagnostic data are used in managing the patient,
the physician may prescribe a course of treatment that places the
patient at risk unnecessarily.

VI. Summary of Reasons for Reclassification

    FDA believes that EPPG devices and PSA devices should be
reclassified from class III to class II because special controls, in
addition to general controls, can be established to provide reasonable
assurance of the safety and effectiveness of the devices, and because
general controls themselves are insufficient to provide reasonable
assurance of their safety and effectiveness. In addition, there is now
sufficient information to establish special controls to provide such
assurance. FDA also believes that TCPSA devices--as a subset of PSA
devices--can achieve a reasonable assurance of safety and effectiveness
using the same special controls proposed for EPPG and PSA devices with
the addition of limiting use to the duration of the implant procedure
in order to mitigate the risk of unwanted interventricular stimulation
leading to arrhythmia (captured as misdiagnosis and improper pacing
leading to unwanted stimulation in the list of risks to health in
section V).

VII. Summary of Data Upon Which the Reclassification Is Based

A. EPPG Devices

    FDA believes that the identified special controls, in addition to
general controls, are necessary to provide reasonable assurance of
safety and effectiveness of these devices. Therefore, in accordance
with sections 513(e) and 515(i) of the FD&C Act and Sec.  860.130,
based on new information with respect to the device and taking into
account the public health benefit of the use of the device and the
nature and known incidence of the risk of the device, FDA, on its own
initiative, is proposing to reclassify this preamendments class III
device into class II. The Agency has identified special controls that
would provide reasonable assurance of their safety and effectiveness.
EPPG are prescription devices restricted to patient use only upon the
authorization of a practitioner licensed by law to administer or use
the device. Since 1979 when FDA classified EPPG devices into class III,
sufficient evidence has been developed to support a reclassification to
class II with the establishment of special controls. FDA has been
reviewing these devices for many years and their risks are well known.
The risks to health are identified in section V, and FDA believes these
risks can be adequately mitigated by special controls.
    EPPG devices that use temporary cardiac pacing for the purposes of
rate control or treatment of bradycardia use mature technology with
well-established evidence of effectiveness (Refs. 3, 8, 9, 11, 13). A
review of 14 clinical studies published over four decades shows that
temporary external pacing is generally safe and has an
electrophysiologic as well as hemodynamic benefit when used as
indicated (Refs. 3 to 17).
    The low frequency of serious adverse events as evidenced through
FDA's Manufacturer and User Facility Device Experience (MAUDE)
database, the low rate of postmarket recalls, the established
scientific evidence to support pacing for specific indications, the
hospital use environment, and FDA's review experience with these
devices, all support the reclassification of these devices to class II.
In addition, several key performance standards (such as IEC 60601-1 and
IEC 60601-2-31) that address various aspects of design and performance
have been developed and used to support marketing applications since
the original classification. In light of these considerations, FDA has
tentatively concluded that the identified special controls, in addition
to general controls, provide reasonable assurance of the safety and
effectiveness of EPPG devices.
    FDA's presentation to the 2013 Panel included a summary of the
available safety and effectiveness information for EPPG devices,
including adverse event reports from FDA's MAUDE database and available
literature. Based on the available scientific literature, which
supports that use of EPPG devices may be beneficial for patients
needing temporary atrial and/or ventricular pacing, FDA recommended to
the 2013 Panel that EPPG devices be reclassified to class II (special
controls). The 2013 Panel discussed and made recommendations regarding
the regulatory classification of EPPG devices to either reconfirm to
class III (subject to premarket approval application) or reclassify to
class II (subject to special controls). The 2013 Panel agreed with
FDA's conclusion that the available scientific evidence is adequate to
support the safety and effectiveness of EPPG devices. The 2013 Panel
also acknowledged that EPPG devices are life-supporting devices and
provided the following rationale per

Sec.  860.93 for recommending that EPPG devices be reclassified to
class II: (1) These devices are used exclusively in the hospital
environment where backup monitoring is available, hazards can be
recognized and treated immediately, and where there is a reasonable
expectation that users are adequately trained; (2) there is sufficient
clinical experience that attests to the benefit of the device; and (3)
the recommended special controls will mitigate the health risks
associated with the device.
    The 2013 Panel also agreed with the identified risks to health
presented at the meeting; however, it recommended that FDA consider
rewording some of the language for clarity and also to ensure that
certain hazards, such as asynchronous pacing and arrhythmia induction,
are included in the risks to health. FDA agrees with the 2013 Panel's
recommendations and modified the risks to health accordingly as
outlined in section V. The 2013 Panel also agreed with FDA's proposed
special controls outlined in section VIII; however, the 2013 Panel
further recommended that FDA add labeling requirements for proper
training, proper maintenance of the device, and remedial actions for
failures due to lead connections. FDA agrees with the 2013 Panel and
the proposed special controls have been modified to reflect more
specific labeling requirements.
    The 2013 Panel transcript and other meeting materials are available
on FDA's Web site (Ref. 2).

B. PSA Devices

    FDA believes that the identified special controls, in addition to
general controls, are necessary to provide reasonable assurance of
safety and effectiveness of these devices. Therefore, in accordance
with sections 513(e) and 515(i) of the FD&C Act and Sec.  860.130,
based on new information with respect to the device and taking into
account the public health benefit of the use of the device and the
nature and known incidence of the risks of the device, FDA, on its own
initiative, is proposing to reclassify these class III devices into
class II. The Agency has identified special controls that would provide
reasonable assurance of their safety and effectiveness.
    Single and dual chamber PSA devices combine the functions of a
pacemaker electrode function tester (class II) and an EPPG device
(proposed class II). No new risks have been identified from the
combination of these devices and the 2013 Panel likewise did not
identify new concerns with regulating single and dual chamber PSAs in a
manner consistent with EPPG devices. The low frequency of serious
adverse events as evidenced through FDA's MAUDE database, the low rate
of postmarket recalls, the established scientific evidence to support
pacing for specific indications, the hospital use environment, and
FDA's review experience with these devices, all supports the
reclassification of these devices to class II. These devices are
prescription devices restricted to patient use only upon the
authorization of a practitioner licensed by law to administer or use
the device.
    Sufficient evidence has been developed to support a
reclassification of single and dual chamber PSA devices, to class II
with special controls. FDA has been reviewing these devices for many
years and their risks are well known. The risks to health are
identified in section V, and FDA believes these risks can be adequately
mitigated by general and special controls.
    Sufficient evidence has also been developed to support a
reclassification of TCPSA devices. FDA has not identified any
additional risks to the patient due to the availability to pace three
chambers in terms of failure to pace or improper pacing rate during the
implant procedure. The longer-term hemodynamic issues associated with
biventricular pacing are not relevant to the acute implant procedure.
The use of TCPSAs is limited by labeling to use only during implant of
a pacemaker or implantable cardioverter defibrillator (ICD).
Accordingly, the proposed special controls for TCPSA devices contain
the same requirements as EPPG devices with the addition of labeling
that indicates TCPSA use only during the implant procedure.
    FDA's presentation to the 2013 Panel included a summary of the
available safety and effectiveness information for TCPSA devices,
including adverse event reports from FDA's MAUDE database and a search
of the available literature. The searches did not identify any safety
issues for this device type.
    Based on the available evidence, FDA recommended to the 2013 Panel
that TCPSA devices be reclassified to class II (special controls). The
2013 Panel discussed and made recommendations regarding the regulatory
classification of TCPSA devices to either reconfirm to class III
(subject to premarket approval application) or reclassify to class II
(subject to special controls) as directed by section 513(e) of the FD&C
Act. The 2013 Panel agreed with FDA's conclusion that the available
scientific evidence is adequate to support the safety and effectiveness
of TCPSA devices and reclassify them to class II. The 2013 Panel also
acknowledged that TCPSA devices are life-supporting devices and
provided the following rationale per Sec.  860.93 for recommending that
TCPSA devices be reclassified to class II: (1) These devices are used
only during the implant procedure where backup monitoring is
continuous, hazards can be recognized and treated immediately, and
where there is a reasonable expectation that users are adequately
trained; (2) these devices are not intended to provide the long-term
hemodynamic benefit of biventricular pacing or cardiac
resynchronization therapy; and (3) the recommended special controls
will mitigate the health risks associated with the device.
    The 2013 Panel also agreed with the identified risks to health
presented at the meeting; however, the 2013 Panel recommended that FDA
consider the same modifications as recommended for EPPG devices. FDA
agrees with the 2013 Panel's recommendations and modified the risks to
health accordingly as outlined in section V. The 2013 Panel also agreed
with FDA's proposed special controls outlined in section VIII; however,
the 2013 Panel further recommended that FDA add labeling requirements
for proper training, proper maintenance of the device, and remedial
actions for failures due to lead connections. FDA agrees with the 2013
Panel.
    The 2013 Panel transcript and other meeting materials are available
on FDA's Web site (Ref. 2).

VIII. Proposed Special Controls

A. EPPG Devices

    FDA believes that the following special controls, together with
general controls (including applicable prescription-use restrictions
and continuing 510(k) notification requirements), are sufficient to
mitigate the risks to health described in section V for EPPG devices:
    1. Appropriate analysis/testing must validate electromagnetic
compatibility (EMC) within a hospital environment.
    2. Electrical bench testing must demonstrate device safety during
intended use. This must include testing with the specific power source
(i.e., battery power, AC mains connections, or both).
    3. Non-clinical performance testing data must demonstrate the
performance characteristics of the device. Testing must include the
following:
     Testing must demonstrate the accuracy of monitoring
functions, alarms, measurement features, therapeutic features, and all
adjustable

or programmable parameters as identified in labeling;
     mechanical bench testing of material strength must
demonstrate that the device and connection cables will withstand forces
or conditions encountered during use;
     simulated use analysis/testing must demonstrate adequate
user interface for adjustable parameters, performance of alarms,
display screens, interface with external devices (e.g. data storage,
printing), and indicator(s) functionality under intended use
conditions; and
     methods and instructions for cleaning the pulse generator
and connection cables must be validated.
    4. Appropriate software verification, validation, and hazard
analysis must be performed.
    5. Labeling must include the following:
     The labeling must clearly state that these devices are
intended for use in a hospital environment and under the supervision of
a clinician trained in its use;
     connector terminals should be clearly, unambiguously
marked on the outside of the EPPG device. The markings should identify
positive (+) and negative (-) polarities. Dual chamber devices should
clearly identify atrial and ventricular terminals;
     the labeling must list all pacing modes available in the
device;
     labeling must include a detailed description of any
special capabilities (e.g., overdrive pacing or automatic mode
switching); and
     appropriate electromagnetic compatibility information must
be included.
    Table 1 shows how FDA believes that the risks to health identified
in section V can be mitigated by the proposed special controls.

     Table 1--Health Risks and Mitigation Measures for EPPG Devices
------------------------------------------------------------------------
           Identified risk                    Mitigation measures
------------------------------------------------------------------------
Failure to Pace......................  Use Environment.
                                       EMC Testing.
                                       Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Improper High Rate Pacing............  Use Environment.
                                       EMC Testing.
                                       Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Pacing at an Improperly Low Rate.....  Use Environment.
                                       EMC Testing.
                                       Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Improper Pacing Leading to Unwanted    Non-Clinical Performance
 Stimulation.                           Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Micro/Macro Shock....................  Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Labeling.
------------------------------------------------------------------------

    In addition, under Sec.  801.109, the sale, distribution, and use
of EPPG devices are restricted to prescription use. Prescription use
restrictions are a type of general control in section 513(a)(1)(A)(i)
of the FD&C Act. Also, under Sec.  807.81, the device would continue to
be subject to 510(k) notification requirements.

B. PSA Devices

    FDA believes that the following special controls, together with
general controls (including applicable prescription-use restrictions
and continuing 510(k) notification requirements), are sufficient to
mitigate the risks to health described in section V for single, dual,
and triple chamber PSA devices:
    1. Appropriate analysis/testing must validate EMC within a hospital
environment.
    2. Electrical bench testing must demonstrate device safety during
intended use. This must include testing with the specific power source
(i.e., battery power, AC mains connections, or both).
    3. Non-clinical performance testing data must demonstrate the
performance characteristics of the device. Testing must include the
following:
     Testing must demonstrate the accuracy of monitoring
functions, alarms, measurement features, therapeutic features, and all
adjustable or programmable parameters as identified in labeling;
     mechanical bench testing of material strength must
demonstrate that the device and connection cables will withstand forces
or conditions encountered during use;
     simulated use analysis/testing must demonstrate adequate
user interface for adjustable parameters, performance of alarms,
display screens, interface with external devices (e.g. data storage,
printing), and indicator(s) functionality under intended use
conditions; and
     methods and instructions for cleaning the pulse generator
and connection cables must be validated.
    4. Appropriate software verification, validation, and hazard
analysis must be performed.
    5. Labeling must include the following:
     The labeling must clearly state that these devices are
intended for use in a hospital environment and under the supervision of
a clinician trained in its use;
     connector terminals should be clearly, unambiguously
marked on the outside of the EPPG device. The markings should identify
positive (+) and negative (-) polarities. Dual

chamber devices should clearly identify atrial and ventricular
terminals. Triple chamber devices should clearly identify atrial, right
ventricular, and left ventricular terminals;
     the labeling must list all pacing modes available in the
device;
     labeling must include a detailed description of any
special capabilities (e.g., overdrive pacing or automatic mode
switching);
     labeling must limit the use of external pacing to the
implant procedure; and
     appropriate electromagnetic compatibility information must
be included.
    Table 2 shows how FDA believes that the risks to health identified
in section V can be mitigated by the proposed special controls.

      Table 2--Health Risks and Mitigation Measures for PSA Devices
------------------------------------------------------------------------
           Identified risk                    Mitigation measures
------------------------------------------------------------------------
Misdiagnosis.........................  Non-Clinical Performance
                                        Evaluation.
                                       Labeling.
Failure to Pace......................  Use Environment.
                                       EMC Testing.
                                       Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Improper High Rate Pacing............  Use Environment.
                                       EMC Testing.
                                       Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Pacing at an Improperly Low Rate.....  Use Environment.
                                       EMC Testing.
                                       Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Improper Pacing Leading to Unwanted    Non-Clinical Performance
 Stimulation.                           Evaluation.
                                       Software Verification, Validation
                                        & Hazards Analysis.
                                       Labeling.
Micro/Macro Shock....................  Electrical Safety Testing.
                                       Non-Clinical Performance
                                        Evaluation.
                                       Labeling.
------------------------------------------------------------------------

    In addition, under Sec.  801.109, the sale, distribution, and use
of these single and dual chamber PSA devices are restricted to
prescription use. Prescription use restrictions are a type of general
controls in section 513(a)(1)(A)(i) of the FD&C Act. Also, under Sec.
807.81, the device would continue to be subject to 510(k) notification
requirements.

IX. Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this 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.

X. Paperwork Reduction Act of 1995

    This proposed order refers to currently 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 part 807, subpart E, have been approved
under OMB control number 0910-0120; the collections of information in
21 CFR part 814, subpart B, have been approved under OMB control number
0910-0231; and the collections of information under 21 CFR part 801
have been approved under OMB control number 0910-0485.

XI. Codification of Orders

    Prior to the amendments by FDASIA, section 513(e) of the FD&C Act
provided for FDA to issue regulations to reclassify devices. Although
section 513(e) as amended authorizes FDA to issue orders rather than
regulations, FDASIA also provides for FDA to revoke previously issued
regulations by order. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as changes to
codified classification determinations or as newly codified orders.
Therefore, under section 513(e)(1)(A)(i) of the FD&C Act, as amended by
FDASIA, in this proposed order we are proposing to: (1) Revoke the
requirements in Sec.  870.3600 related to the classification of EPPG
devices as class III devices and to codify the reclassification of EPPG
devices into class II (special controls) and (2) codify the
reclassification of PSA devices into class II (special controls).

XII. Proposed Effective Date

    FDA is proposing that any final order based on this proposed order
become effective on the date of its publication in the Federal Register
or at a later date if stated in the final order.

XIII. Comments

    Comments already submitted to the docket (FDA-2011-N-0650) have
been officially noted and do not need to be resubmitted. FDA will
consider previous docket comments in issuing any final orders for these
devices. Interested persons may submit either electronic comments
regarding this document or the associated guidance 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.

XIV. 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,
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. Class II Special Controls Draft Guidance Document: External
Pacemaker Pulse Generator, available at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM275703.pdf.
2. The panel transcript and other meeting materials for the
September 11, 2013, Circulatory System Devices Panel are available
on FDA's Web site at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/CirculatorySystemDevicesPanel/ucm342357.htm.
3. ``ACC/AHA Guidelines for the Management of Patients with ST-
Elevation Myocardial Infarction,'' Circulation, 110:e82-e292, 2004.
4. Beland, M. J., P. S. Hesslein, C. D. Finlay, et al.,
``Noninvasive Transcutaneous Cardiac Pacing in Children,'' Pacing
and Clinical Electrophysiology, 10:1262-1270, 1987.
5. Braun, M. U., T. Rauwolf, M. Bock, et al., ``Percutaneous Lead
Implantation Connected to an External Device in Stimulation-
Dependent Patients With Systemic Infection--A Prospective and
Controlled Study,'' Pacing and Clinical Electrophysiology, August;
29(8):875-879, 2006.
6. Ceresnak, S. R., R. H. Pass, T. J. Starc, et al., ``Predictors
for Hemodynamic Improvement With Temporary Pacing After Pediatric
Cardiac Surgery,'' Journal of Thoracic Cardiovascular Surgery,
January; 141(1):183-187, 2011.
7. Dunn, D. L. and J. J. Gregory, ``Noninvasive Temporary Pacing:
Experience in a Community Hospital,'' Heart and Lung, January;
18(1):23-28, 1989.
8. Eberhardt, F., T. Hanke, M. Heringlake, et al., ``Feasibility of
Temporary Biventricular Pacing in Patients With Reduced Left
Ventricular Function After Coronary Artery Bypass Grafting,'' Pacing
and Clinical Electrophysiology, January; 30 Suppl 1:S50-53, 2007.
9. Ferguson, T. B. Jr. and J. L. Cox, ``Temporary External DDD
Pacing After Cardiac Operations,'' The Annals of Thoracic Surgery,
May; 51(5):723-732, 1991.
10. Halldorsson, A. O., W. T. Vigneswaran, F. J. Podbielski, and D.
M. Evans, ``Electrophysiological and Clinical Comparison of Two
Temporary Pacing Leads Following Cardiac Surgery,'' Pacing and
Clinical Electrophysiology, August; 22(8):1221-1225, 1999.
11. Hindman, M. C., G. S. Wagner, M. JaRo, et al., ``The Clinical
Significance of Bundle Branch Block Complicating Acute Myocardial
Infarction. Indications for Temporary and Permanent Pacemaker
Insertion,'' Circulation, October; 58(4):689-699, 1978.
12. Janousek J., P. Vojtovic, and R. A. Gebauer, ``Use of a
Modified, Commercially Available Temporary Pacemaker for R Wave
Synchronized Atrial Pacing in Postoperative Junctional Ectopic
Tachycardia,'' Pacing and Clinical Electrophysiology, February; 26(2
Pt. 1):579-586, 2003.
13. Kratz, J. and J. Tyler, ``Clinical Experience with a New DDD
External Pacemaker,'' Pacing and Clinical Electrophysiology,
December; 16(12):2227-2234, 1993.
14. Nimetz, A. A., S. J. Shubrooks, A. M. Hutter, and R. W.
DeSanctis, ``The Significance of Bundle Branch Block During Acute
Myocardial Infarction,'' American Heart Journal, October; 90(4):439-
444, 1975.
15. Pinneri, F., S. Frea, K. Najd, et al., ``Echocardiography-Guided
Versus Fluoroscopy-Guided Temporary Pacing in the Emergency Setting:
An Observational Study,'' Journal of Cardiovascular Medicine
(Hagerstown), March; 14(3):242-246, 2013.
16. Siddons, H., ``Transvenous Long-Term Pacing With an External
Pacemaker. What Are the Risks?'', Pacing and Clinical
Electrophysiology, April; 1(2):163-165, 1978.
17. Voigtl[auml]nder T., B, Nowak, P. B[auml]renf[auml]nger, et al.,
``Feasibility and Sensing Thresholds of Temporary Single-Lead VDD
Pacing in Intensive Care,'' American Journal of Cardiology, May 15;
79(10):1360-1363, 1997.

List of Subjects in 21 CFR Part 870

    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 870 be amended as follows:

PART 870--CARDIOVASCULAR DEVICES

0
1. The authority citation for 21 CFR part 870 continues to read as
follows:

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

0
2. Section 870.3600 is revised to read as follows:

Sec.  870.3600  External pacemaker pulse generator.

    (a) Identification. An external pacemaker pulse generator (EPPG) is
a prescription device that has a power supply and electronic circuits
that produce a periodic electrical pulse to stimulate the heart. This
device, which is used outside the body, is used as a temporary
substitute for the heart's intrinsic pacing system until a permanent
pacemaker can be implanted, or to control irregular heartbeats in
patients following cardiac surgery or a myocardial infarction. The
device may have adjustments for impulse strength, duration, R-wave
sensitivity, and other pacing variables.
    (b) Classification. Class II (special controls). The special
controls for this device are:
    (1) Appropriate analysis/testing must validate electromagnetic
compatibility (EMC) within a hospital environment.
    (2) Electrical bench testing must demonstrate device safety during
intended use. This must include testing with the specific power source
(i.e., battery power, AC mains connections, or both).
    (3) Non-clinical performance testing data must demonstrate the
performance characteristics of the device. Testing must include the
following:
    (i) Testing must demonstrate the accuracy of monitoring functions,
alarms, measurement features, therapeutic features, and all adjustable
or programmable parameters as identified in labeling;
    (ii) Mechanical bench testing of material strength must demonstrate
that the device and connection cables will withstand forces or
conditions encountered during use;
    (iii) Simulated use analysis/testing must demonstrate adequate user
interface for adjustable parameters, performance of alarms, display
screens, interface with external devices (e.g. data storage, printing),
and indicator(s) functionality under intended use conditions; and
    (iv) Methods and instructions for cleaning the pulse generator and
connection cables must be validated.
    (4) Appropriate software verification, validation, and hazard
analysis must be performed.
    (5) Labeling must include the following:
    (i) The labeling must clearly state that these devices are intended
for use in a hospital environment and under the supervision of a
clinician trained in their use; and
    (ii) Connector terminals should be clearly, unambiguously marked on
the outside of the EPPG device. The markings should identify positive
(+) and negative (-) polarities. Dual chamber devices should clearly
identify atrial and ventricular terminals; and
    (iii) The labeling must list all pacing modes available in the
device;

    (iv) Labeling must include a detailed description of any special
capabilities (e.g., overdrive pacing or automatic mode switching); and
    (v) Appropriate electromagnetic compatibility information must be
included.
0
3. In Subpart D, add Sec.  870.3605 to read as follows:

Sec.  870.3605  Pacing system analyzer.

    (a) Identification. A pacing system analyzer (PSA) is a
prescription device that combines the functionality of a pacemaker
electrode function tester (Sec.  870.3720) and an external pacemaker
pulse generator (EPPG) (Sec.  870.3600). It is connected to a pacemaker
lead and uses a power supply and electronic circuits to supply an
accurately calibrated, variable pacing pulse for measuring the
patient's pacing threshold and intracardiac R-wave potential. A PSA may
be a single, dual, or triple chamber system and can simultaneously
deliver pacing therapy while testing one or more implanted pacing
leads.
    (b) Classification. Class II (special controls) for PSAs. The
special controls for this device are:
    (1) Appropriate analysis/testing must validate electromagnetic
compatibility (EMC) within a hospital environment.
    (2) Electrical bench testing must demonstrate device safety during
intended use. This must include testing with the specific power source
(i.e., battery power, AC mains connections, or both).
    (3) Non-clinical performance testing data must demonstrate the
performance characteristics of the device. Testing must include the
following:
    (i) Testing must demonstrate the accuracy of monitoring functions,
alarms, measurement features, therapeutic features, and all adjustable
or programmable parameters as identified in labeling;
    (ii) Mechanical bench testing of material strength must demonstrate
that the device and connection cables will withstand forces or
conditions encountered during use;
    (iii) Simulated use analysis/testing must demonstrate adequate user
interface for adjustable parameters, performance of alarms, display
screens, interface with external devices (e.g. data storage, printing),
and indicator(s) functionality under intended use conditions; and
    (iv) Methods and instructions for cleaning the pulse generator and
connection cables must be validated.
    (4) Appropriate software verification, validation, and hazard
analysis must be performed.
    (5) Labeling must include the following:
    (i) The labeling must clearly state that these devices are intended
for use in a hospital environment and under the supervision of a
clinician trained in their use;
    (ii) Connector terminals should be clearly, unambiguously marked on
the outside of the EPPG. The markings should identify positive (+) and
negative (-) polarities. Dual chamber devices should clearly identify
atrial and ventricular terminals. Triple chamber devices should clearly
identify atrial, right ventricular, and left ventricular terminals;
    (iii) The labeling must list all pacing modes available in the
device;
    (iv) Labeling must include a detailed description of any special
capabilities (e.g., overdrive pacing or automatic mode switching);
    (v) Labeling must limit the use of external pacing to the implant
procedure; and
    (vi) Appropriate electromagnetic compatibility information must be
included.

    Dated: September 9, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-21814 Filed 9-12-14; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 76, Number 108 (Monday, June 6, 2011)]
[Notices]
[Pages 32369-32370]
[FR Doc No: 2011-13916]

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

DEPARTMENT OF HOMELAND SECURITY

Federal Emergency Management Agency

[Internal Agency Docket No. FEMA-3318-EM; Docket ID FEMA-2011-0001]

North Dakota; Amendment No. 4 to Notice of an Emergency
Declaration

AGENCY: Federal Emergency Management Agency, DHS.

ACTION: Notice.

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

SUMMARY: This notice amends the notice of an emergency declaration for
the State of North Dakota (FEMA-3318-EM), dated April 7, 2011, and
related determinations.

DATES: Effective Date: May 28, 2011.

FOR FURTHER INFORMATION CONTACT: Peggy Miller, Office of Response and
Recovery, Federal Emergency Management Agency, 500 C Street, SW.,
Washington, DC 20472,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION: The notice of an emergency declaration for
the State of North Dakota is hereby amended to include the following
areas among those areas determined to have been adversely affected by
the event declared an emergency by the President in his declaration of
April 7, 2011.

    Burleigh, Emmons, McLean, Mercer, Morton, Oliver, and Sioux
Counties and the portion of the Standing Rock Reservation within the
State of North Dakota for emergency protective measures (Category
B), limited to direct Federal assistance, under the Public
Assistance program.

The following Catalog of Federal Domestic Assistance Numbers (CFDA)
are to be used for reporting and drawing funds: 97.030, Community
Disaster Loans; 97.031, Cora Brown Fund; 97.032, Crisis Counseling;
97.033, Disaster Legal Services; 97.034, Disaster Unemployment
Assistance (DUA); 97.046, Fire Management Assistance Grant; 97.048,
Disaster Housing Assistance to Individuals and Households In
Presidentially Declared Disaster Areas; 97.049, Presidentially
Declared Disaster Assistance--Disaster Housing Operations for
Individuals and Households; 97.050, Presidentially Declared Disaster
Assistance to Individuals and Households--Other Needs; 97.036,
Disaster Grants--Public Assistance (Presidentially Declared
Disasters); 97.039, Hazard Mitigation Grant.

W. Craig Fugate,
Administrator, Federal Emergency Management Agency.
[FR Doc. 2011-13916 Filed 6-3-11; 8:45 am]
BILLING CODE 9111-23-P


[Federal Register Volume 87, Number 212 (Thursday, November 3, 2022)]
[Notices]
[Pages 66309-66310]
[FR Doc No: 2022-23866]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-D-2107]

Cross Labeling Oncology Drugs in Combination Regimens; Guidance
for Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

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

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of a final guidance for industry entitled ``Cross
Labeling Oncology Drugs in Combination Regimens.'' This guidance
describes FDA's current recommendations on including relevant
information in labeling for oncology drugs approved for use in
combination regimens. This guidance finalizes the draft guidance of the
same title issued on November 20, 2020.

DATES: The announcement of the guidance is published in the Federal
Register on November 3, 2022.

ADDRESSES: You may submit either electronic or written comments on
Agency guidances at any time as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and

identified, as confidential, if submitted as detailed in
``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2020-D-2107 for ``Cross Labeling Oncology Drugs in Combination
Regimens.'' Received comments will be placed in the docket and, except
for those submitted as ``Confidential Submissions,'' publicly viewable
at https://www.regulations.gov or at the Dockets Management Staff
between 9 a.m. and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://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 Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.
    You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
    Submit written requests for single copies of this guidance to the
Division of Drug Information, Center for Drug Evaluation and Research,
Food and Drug Administration, 10001 New Hampshire Ave., Hillandale
Building, 4th Floor, Silver Spring, MD 20993-0002; or the Office of
Communication, Outreach, and Development, Center for Biologics
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring, MD 20993-0002. Send
one self-addressed adhesive label to assist that office in processing
your requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.

FOR FURTHER INFORMATION CONTACT: Marc Theoret, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 22, Rm. 2218, Silver Spring, MD 20993, 301-796-
4099; or Stephen Ripley, Center for Biologics Evaluation and Research,
Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 71, Rm.
7301, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a guidance for industry
entitled ``Cross Labeling Oncology Drugs in Combination Regimens.''
This guidance describes FDA's current recommendations on including
relevant information in labeling for oncology drugs approved for use in
combination regimens.
    This guidance finalizes the draft guidance of the same title issued
on November 20, 2020 (85 FR 74352). FDA considered comments received on
the draft guidance as the guidance was finalized. Changes from the
draft to the final guidance include clarity on our recommendations for
the content of each section of the prescribing information, including
how doses or dosage modifications for any other drug in the combination
regimen should be described in labeling.
    This guidance is being issued consistent with FDA's good guidance
practices regulation (21 CFR 10.115). The guidance represents the
current thinking of FDA on ``Cross Labeling Oncology Drugs in
Combination Regimens.'' It does not establish any rights for any person
and is not binding on FDA or the public. You can use an alternative
approach if it satisfies the requirements of the applicable statutes
and regulations.

II. Paperwork Reduction Act of 1995

    While this guidance contains no collection of information, it does
refer to previously approved FDA collections of information. Therefore,
clearance by the Office of Management and Budget (OMB) under the
Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521) is not
required for this guidance. The previously approved collections of
information are subject to review by OMB under the PRA. The collections
of information in 21 CFR part 314, including the submission of labeling
in 21 CFR 314.50(e)(2)(ii) and (l)(1)(i) and the submission of new drug
applications (NDAs) and supplemental NDAs, have been approved under OMB
control number 0910-0001. The collections of information in 21 CFR part
312 regarding the submission of investigational new drug applications
have been approved under OMB control number 0910-0014. The collections
of information for the content and format of prescription drug labeling
in 21 CFR 201.56 and 201.57 have been approved under OMB control number
0910-0572. The collections of information in FDA's guidance entitled
``Formal Meetings Between FDA and Sponsors and Applicants for PDUFA
Products'' have been approved under OMB control number 0910-0429.

III. Electronic Access

    Persons with access to the internet may obtain the guidance at
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs, https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.

    Dated: October 28, 2022.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2022-23866 Filed 11-2-22; 8:45 am]
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