[Federal Register Volume 81, Number 14 (Friday, January 22, 2016)]
[Proposed Rules]
[Pages 3751-3762]
[FR Doc No: 2016-01173]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 882

[Docket No. FDA-2014-N-1209]

Neurological Devices; Reclassification of Cranial Electrotherapy
Stimulator Intended To Treat Insomnia and/or Anxiety; Effective Date of
Requirement for Premarket Approval for Cranial Electrotherapy
Stimulator Intended To Treat Depression

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed
administrative order to reclassify the cranial electrotherapy
stimulator (CES) devices intended to treat insomnia and/or anxiety, a
preamendments class III device, into class II (special controls) and
subject to premarket notification, and to require the filing of a
premarket approval application (PMA) for CES devices intended to treat
depression. FDA is proposing the reclassification of CES devices
intended to treat insomnia and/or anxiety under the Federal Food, Drug,
and Cosmetic Act (the FD&C Act) based on new information pertaining to
the device. This proposed action would implement certain statutory
requirements. FDA is also clarifying the identification for CES devices
in this proposed order by identifying CES as a prescription device that
applies electrical current that is not intended to induce a seizure to
a patient's head to treat psychiatric conditions. This clarification
distinguishes CES from electroconvulsive therapy (ECT).

DATES: Submit either electronic or written comments on this proposed
order by April 21, 2016. See sections IX and XVII of this document for,
respectively, the proposed dates when the new requirements apply and
the proposed effective date of a final order based on this proposed
order.

ADDRESSES: You may submit comments as follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to http://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 http://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): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Division of
Dockets Management, 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-2014-N-1209 for ``Neurological Devices; Reclassification of Cranial
Electrotherapy Stimulator (CES) Intended to Treat Insomnia and/or
Anxiety; Effective Date of Requirement for Premarket Approval for CES
Intended to Treat Depression.'' Received comments will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at http://www.regulations.gov or at the Division of
Dockets Management between 9 a.m. and 4 p.m., Monday through Friday.
     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 http://www.regulations.gov.
Submit both copies to the Division of Dockets Management. 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: http://www.fda.gov/regulatoryinformation/dockets/default.htm.
    Docket: For access to the docket to read background documents or
the electronic and written/paper 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: Michael Ryan, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 1615, Silver Spring, MD 20993,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    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 (SMDA) (Pub. L. 101-629), Food and Drug Administration
Modernization Act of 1997 (FDAMA) (Pub. L. 105-115), the Medical Device
User Fee and Modernization Act of 2002 (MDUFMA) (Pub. L. 107-250), the
Medical Devices Technical Corrections Act (Pub. L. 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), among other amendments, 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).
    Under section 513(d) 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 (both the preamendments and substantially
equivalent devices are referred to as preamendments class III devices)
may be marketed without submission of a PMA until FDA issues a final
order under section 515(b) of the FD&C Act (21 U.S.C. 360e(b))
requiring premarket approval.
    Although under the FD&C Act the manufacturer of a preamendments
class III device may respond to the call for PMAs by filing a PMA or a
notice of completion of a product development protocol (PDP), in
practice the option of filing a notice of completion of a PDP has not
been used. For simplicity, although corresponding requirements for PDPs
remain available to manufacturers in response to a final order under
section 515(b) of the FD&C Act, this document will refer only to the
requirement for the filing and receiving approval of a PMA.
    On July 9, 2012, FDASIA was enacted. Sections 608(a) and (b) of
FDASIA (126 Stat. 1056) amended sections 513(e) and 515(b) of the FD&C
Act, changing the mechanism for, respectively, reclassifying a device
and requiring premarket approval for a preamendments class III device
from rulemaking to an administrative order.

A. Reclassification

    FDA is publishing this document to propose the reclassification of
CES devices to treat insomnia and/or anxiety from class III to class
II.
    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)
of the FD&C Act 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 Department of Health, Education, and 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).)

    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, 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.''
(Upjohn, 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) (21 CFR
860.7(c)(2)). (See, e.g., General Medical Co. v. FDA, 770 F.2d 214
(D.C. Cir. 1985); Contact Lens Mfrs. Ass'n 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
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 for reclassifying a device. 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 to a
public docket. To meet these requirements, FDA has held a meeting of a
device classification panel described in section 513(b) of the FD&C Act
with respect to CES devices and is publishing in the Federal Register
this proposed order to reclassify CES devices intended to treat
insomnia and/or anxiety.
    FDAMA added section 510(m) to 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 provide reasonable assurance of safety and effectiveness
of the device. FDA has determined that premarket notification is
necessary to provide reasonable assurance of safety and effectiveness
of CES devices intended for treating insomnia and/or anxiety and,
therefore, this device type is not exempt from premarket notification
requirements.

B. Requirement for Premarket Approval Application

    FDA is proposing to require PMAs for CES devices intended to treat
depression. Section 515(b)(1) of the FD&C Act sets forth the process
for issuing a final order requiring PMAs. Specifically, prior to the
issuance of a final order requiring premarket approval for a
preamendments class III 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. FDA has held a
meeting of a device classification panel described in section 513(b) of
the FD&C Act with respect to CES devices and is publishing in the
Federal Register this proposed order calling for PMAs for CES devices
intended to treat depression.
    Section 515(b)(2) of the FD&C Act provides that a proposed order to
require premarket approval shall contain: (1) The proposed order, (2)
proposed findings with respect to the degree of risk of illness or
injury designed to be eliminated or reduced by requiring the device to
have an approved PMA or a declared completed PDP and the benefit to the
public from the use of the device, (3) an opportunity for the
submission of comments on the proposed order and the proposed findings,
and (4) an opportunity to request a change in the classification of the
device based on new information relevant to the classification of the
device.
    Section 515(b)(3) of the FD&C Act provides that FDA shall, after
the close of the comment period on the proposed order, consideration of
any comments received, and a meeting of a device classification panel
described in section 513(b) of the FD&C Act, issue a final order to
require premarket approval or publish a document terminating the
proceeding together with the reasons for such termination. If FDA
terminates the proceeding, FDA is required to initiate reclassification
of the device under section 513(e) of the FD&C Act, unless the reason
for termination is that the device is a banned device under section 516
of the FD&C Act (21 U.S.C. 360f).
    Under section 501(f) of the FD&C Act (21 U.S.C. 351(f)), a
preamendments class III device may be commercially distributed without
a PMA until 90 days after FDA issues a final order (or a final rule
issued under section 515(b) of the FD&C Act prior to the enactment of
FDASIA) requiring premarket approval for the device, or 30 months after
final classification of the device under section 513 of the FD&C Act,
whichever is later. For CES devices, the preamendments class III
devices that are the subject of this proposal, the later of these two
time periods is the 90-day period. Since these devices were classified
in 1979, the 30-month period has expired (44 FR 51770, September, 4,
1979). Therefore, if the proposal to require premarket approval for CES
devices to treat depression is finalized, section 501(f)(2)(B) of the
FD&C Act requires that a PMA for such device be filed within 90 days of
the effective date of the final order. However, FDA does not intend to
enforce compliance with the 90-day deadline for PMA submissions for
currently legally marketed CES devices to treat depression. See further
discussion in section IX ``Dates New Requirements Apply'' for proposed
compliance dates.
    Also, a preamendments device subject to the order process under
section 515(b) of the FD&C Act is not required to have an approved
investigational device exemption (IDE) (see part 812 (21 CFR part 812))
contemporaneous with its interstate distribution until the date
identified by FDA in the final order requiring the filing of a PMA for
the device. At that time, an IDE is required only if a PMA has not been
filed. If the sponsor, manufacturer, or importer of the device submits
an IDE application and FDA approves it, the device may be distributed
for investigational use. If a PMA is not filed by the later of the two
dates (i.e., 180 days after the effective date of the final order), and
the device is not distributed for investigational use under an IDE, the
device is deemed to be adulterated within the meaning of section
501(f)(1)(A) of the FD&C Act, and subject to seizure and condemnation
under section 304 of the FD&C Act (21 U.S.C. 334) if its distribution
continues. Other enforcement actions include, but are not limited to,
the following: Shipment of devices in interstate commerce will be
subject to injunction under section 302 of the FD&C Act (21 U.S.C.
332), and the individuals responsible for such shipment will be subject
to prosecution under section 303 of the FD&C Act (21 U.S.C. 333). In
the past, FDA has requested that manufacturers take action to prevent
the further use of devices for which no PMA or PDP has been filed and
may determine that such a request is appropriate for the class III
devices that are the subject of this proposed order, if finalized.

    In accordance with section 515(b)(2)(D) of the FD&C Act, interested
persons are being offered the opportunity to request reclassification
of CES devices to treat depression.

II. Regulatory History of the Device

    In 1978, the Neurological Devices Panel (the 1978 Panel) discussed
the original classification for the CES device at two separate meetings
(43 FR 55716, November 28, 1978). The 1978 Panel ultimately recommended
that the device be classified into class III because the safety and
effectiveness of the device had not been demonstrated. The 1978 Panel
considered, among other data, information from the National Research
Council, which reviewed 88 published studies on CES and concluded that
the device had not been shown to be effective in treating any of the
conditions for which it was prescribed. In addition, the 1978 Panel
indicated that there was insufficient information to establish an
adequate performance standard for CES because the characteristics of
the electrical current necessary for potential effectiveness were not
known. The 1978 Panel believed that general controls would not provide
sufficient control over these characteristics, and that the device
presented a potential unreasonable risk of illness or injury to the
patient if the practitioner relied on the device instead of more
conventional treatment, and the device was ineffective in treating any
of the conditions for which it was prescribed. FDA agreed with the 1978
Panel's recommendation, and the CES device was classified into class
III in 1979 (44 FR 51770, September 4, 1979).
    In support of a subsequent proposed rule in 1993 to require PMAs
for CES devices (58 FR 45865, August 31, 1993), FDA performed a
literature review and identified additional studies that had been
conducted on the use of CES. After a review of the scientific
literature, FDA concluded that the effectiveness of CES had still not
been established by adequate valid scientific evidence. On August 24,
1995, FDA issued a final rule requiring PMAs (60 FR 43967), but later
proposed to revoke the call for PMAs because the Agency had received
new information and wanted to reconsider the classification of CES and
put out a call for information (62 FR 4023, January 28, 1997) under
section 515(i) of the FD&C Act. The Agency subsequently revoked the
call for PMAs (62 FR 30456, June 4, 1997).
    On April 9, 2009, FDA published a notice for the submission of
safety and effectiveness information on CES devices (74 FR 16214). In
response to that order, FDA received information in support of
reclassification from five device manufacturers that all recommended
CES devices be reclassified to class II. The manufacturers stated that
safety and effectiveness of these devices may be assured by limited
postmarket surveillance; adequate instructions for use, including
warnings about the possibility of unsafe use; availability only upon
the order of a health care professional licensed to diagnose and
differentiate the primary indications of CES for anxiety, insomnia, and
depression from other disorders (i.e., prescription use device); and
compliance with voluntary consensus standards (e.g., for electrical
safety, biocompatibility, etc.).
    On August 8, 2011, FDA published a proposed rule under section
515(b) of the FD&C Act proposing to require PMAs for CES devices (76 FR
48062). In developing the proposed rule, FDA considered literature on
CES devices published since the previous 1993 proposed rule and the
information provided in response to the 2009 notice. FDA concluded from
the review of the scientific literature that the effectiveness of CES
had not been established by adequate valid scientific evidence and the
1978 Panel's original class III recommendation remained appropriate.
The August 8, 2011, proposed rule also provided an opportunity for
interested persons to submit comments on the proposed rule and the
Agency's findings. Under section 515(b)(2) of the FD&C Act, FDA also
provided an opportunity for interested persons to request a change in
the classification of the devices based on new information relevant to
its classification. Any petition requesting a change in classification
of the CES device was required to be submitted by August 23, 2011. The
comment period for the proposed rule closed on November 7, 2011.
    FDA received three petitions conforming to the requirements of
Sec.  860.123 (21 CFR 860.123) requesting a change in the
classification of CES devices. Of these petitions, one requested the
Agency to reclassify CES devices from class III to class II for the
treatment of ``insomnia, depression, or anxiety.'' The second
reclassification petition presented a more focused indication,
requesting the Agency to reclassify CES devices from class III to class
II for the ``treatment of depression, anxiety, and insomnia in adult
substance abuse patients who have failed to achieve satisfactory
improvement from one prior antidepressant or sleep medication at or
above the minimal effective dose and duration in the current episode,
or are unable to tolerate such medication.'' The third reclassification
petition requested the Agency to reclassify CES devices from class III
to class II for the ``general treatment of anxiety, depression, and
insomnia as part of an approved program of medical care when
conventional approaches have failed or are deemed inappropriate'' and
``for the treatment of the primary symptoms of substance abuse:
Anxiety, depression, and insomnia when conventional approaches have
failed or are deemed inappropriate.''
    Consistent with the FD&C Act as it existed at the time, on February
10, 2012, FDA referred the reclassification petitions to the
Neurological Devices Panel (the 2012 Panel) for its recommendation on
the requested change in classification. FDA provided the 2012 Panel
members with the three reclassification petitions and FDA's executive
summary, which included an updated review of the available scientific
literature on the CES device (Ref. 1). Based on its review of the data
as well as information presented during an open meeting (Ref. 2), the
majority of the 2012 Panel did not think there was valid scientific
evidence supporting effectiveness for treatment of insomnia,
depression, or anxiety. However, three 2012 Panel members, including
the industry and patient representatives, did believe there was valid
scientific evidence of effectiveness, and a fourth member believed
effectiveness had been demonstrated for treatment of anxiety but not
for insomnia or depression. The 2012 Panel also pointed out that there
was a lack of device risk, meaning that a benefit/risk analysis might
be favorable with any demonstrated effectiveness. The majority of the
2012 Panel, however, recommended that CES should be kept in class III.
The class III recommendation from the 2012 Panel also applied to the
more focused indication of the two petitioners that requested class II
for use in the substance abuse population, which is an indication
outside the scope of the current classification effort as CES devices
have not been cleared for use in this patient population. The 2012
Panel did not consider, however, the possibility of splitting different
indications into different classifications (though one 2012 Panel
member did state that there seemed to be effectiveness for treatment of
anxiety), or whether there is sufficient evidence to establish clinical
performance testing as a special control. The Agency has since
considered these possibilities, as discussed in this document.

    FDA later issued a proposed administrative order to comply with the
new procedural requirement created by FDASIA when requiring PMAs for a
preamendments class III device (78 FR 20268, April 4, 2013). The
proposed order provided for a comment period that was open until May 6,
2013. FDA received approximately 100 comments related to the CES
device, most suggesting that the device should be reclassified from
class III to class II considering the limited safety risks associated
with the device and the ability to establish special controls to
mitigate the risks to health. FDA also received one additional
reclassification petition requesting that the device be reclassified
from class III to class II.
    On June 12, 2014, FDA withdrew the proposed rule and proposed order
calling for PMAs for CES, stating in the Federal Register notice (79 FR
33712) that the Agency had received over 300 comments to the docket in
response to the proposed rule and proposed order related to CES
devices. Comments that expressed an opinion about the classification of
CES devices were usually in favor of a class II designation. Some
comments did not openly state an opinion, but included arguments
against the proposed rule or order that could reasonably be interpreted
as support for a class II designation. There were also comments that
agreed with a class III designation. The withdrawal also stated that
FDA has considered the information before the Agency, including the
deliberations of the 2012 Panel and the reclassification petitions
submitted for these devices, and has determined that there is
sufficient information to establish special controls, and that these
special controls, together with general controls, will provide a
reasonable assurance of safety and effectiveness for CES devices
intended to treat insomnia and/or anxiety.

III. Device Description

    A CES device is currently defined as a device that applies
electrical current to a patient's head to treat insomnia, depression,
or anxiety. FDA is proposing in this order to modify the identification
language from how it is presently written in Sec.  882.5800(a) (21 CFR
882.5800(a)) for additional clarification. FDA is clarifying in the
identification that these are prescription devices and that the
electrical current should not be intended to induce a seizure in
patients. Clarifying that the stimulation is specifically not intended
to induce a seizure makes a more definitive distinction between CES and
ECT devices. However, FDA does not intend to otherwise describe the
stimulation or electrode placement in the definition. Existing CES
technology encompasses a range of stimulation settings and electrode
placements, and with supportive clinical data, FDA believes that it is
not necessary to establish limitations on the technical characteristics
of CES devices within the definition.

IV. Proposed Reclassification

    FDA is proposing that CES devices intended to treat insomnia and/or
anxiety be reclassified from class III to class II. In order to
reclassify these devices, the Agency must determine that there is
sufficient information to establish special controls that, combined
with the general controls, will provide a reasonable assurance of
device safety and effectiveness. FDA has reconsidered the information
before the Agency, including the deliberations of the 2012 Panel
meeting and the reclassification petitions submitted for these devices,
and has determined that there is sufficient information to establish
special controls to 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 when applied to CES devices intended to treat insomnia
and/or anxiety, including those existing legally marketed devices that
have been previously cleared by FDA in 510(k)s.
    Therefore, in accordance with sections 513(e) and 515(i) of the
FD&C Act and Sec.  860.130 (21 CFR 860.130), based on new information
with respect to the devices 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 when the
device is intended to treat insomnia and/or anxiety. FDA believes that
this new information is sufficient to demonstrate that the proposed
special controls can mitigate the risks to health identified in the
next section, and that these special controls, together with general
controls, will provide a reasonable assurance of safety and
effectiveness for CES devices intended for treating insomnia and/or
anxiety.
    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, are necessary to provide reasonable assurance of their safety
and effectiveness.
    Section 510(m) to the FD&C Act authorizes the Agency to exempt
class II devices from premarket notification (510(k)) requirements. FDA
has considered CES devices intended for treating insomnia and/or
anxiety and decided that the device does require premarket
notification. Therefore, the Agency does not intend to exempt this
proposed class II device from premarket notification (510(k))
submission.

V. Risks to Health

    After considering available information for the classification of
CES devices intended to treat insomnia and/or anxiety, FDA has
determined that the following risks to health are associated with use
of the CES devices:
     Ineffective treatment--If the device is not effective and
the patient is not treated in a conventional manner, the patient's
psychological condition may worsen.
     Skin irritation--The electrodes or the conductive cream
used with the electrodes may cause skin irritation.
     Headaches--Reported cases of adverse effects of CES
devices include headaches following treatment with electrical
stimulation.
     Dizziness--At higher levels of current, patients may
experience feelings of dizziness that subside when the stimulation is
turned down.
     Electrical shock and burns--Malfunction of the device may
result in electrical shock or burns to the user.

VI. Summary of Reasons for Reclassification

    FDA believes that CES devices intended to treat insomnia and/or
anxiety should be reclassified from class III to class II because, in
light of new information about the effectiveness of these devices,
special controls, in addition to general controls, can be established
to provide reasonable assurance of safety and effectiveness of the
device, and because general controls themselves are insufficient to
provide reasonable assurance of its safety and effectiveness. FDA
believes that the risks of the CES devices intended to treat insomnia
and/or anxiety can be mitigated with special controls and that these
mitigations will provide a reasonable assurance of safety for these
devices. Based on a reconsideration of the available information and
data, FDA believes that there is valid scientific evidence of
effectiveness for CES devices in the treatment of insomnia and/or
anxiety. However, because the information available to the Agency
includes evaluations of different CES devices and the methodology of
CES delivery (e.g., electrode placement,

stimulation parameters, duration and frequency of treatment sessions)
varies, the data are insufficient to determine adequate directions for
use and warnings for unsafe use for specific devices, and to determine
whether the devices when used in accordance with such directions will
provide clinically meaningful results. Therefore, it cannot be
concluded, based on available information alone, that there is a
reasonable assurance of effectiveness for individual CES devices
intended to treat insomnia and/or anxiety. However, the available
information for the treatment of insomnia and/or generalized anxiety
with CES devices is sufficient to develop special controls, that
combined with general controls, can provide a reasonable assurance of
safety and effectiveness.

VII. Summary of Data Upon Which the Reclassification Is Based

    FDA believes that the identified special controls, in addition to
general controls (including prescription use restrictions and 510(k)
notification requirements for devices that have not been legally
marketed prior to the effective date of the final order, or devices
that have been legally marketed but are required to submit a new 510(k)
under Sec.  807.81(a)(3) (21 CFR 807.81(a)(3)) because the device is
about to be significantly changed or modified), will provide a
reasonable assurance of safety and effectiveness of CES devices
intended to treat insomnia and/or anxiety. 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(s) of the use of the device and the
nature and known incidence of the risk(s) of the device, FDA is
proposing to reclassify these devices from class III to class II. The
Agency has identified special controls that, when combined with general
controls, are necessary to provide reasonable assurance of their safety
and effectiveness.
    There is a reasonable assurance that a device is effective when it
can be determined, based upon valid scientific evidence, that in a
significant portion of the target population, the use of the device for
its intended uses and conditions of use, when accompanied by adequate
directions for use and warnings against unsafe use, will provide
clinically significant results (see Sec.  860.7(e)(1)). During the 2012
Panel meeting (Ref. 1), the 2012 Panel expressed reservations on
classifying CES devices into class III, given that there are limited
safety concerns associated with these devices, and because they are not
life-supporting or life-sustaining, or of substantial importance in
preventing impairment of human health. The 2012 Panel also suggested
that the list of significant risks in the 2011 proposed rule (76 FR
48062) was not accurate. There was consensus on the risks of skin
irritation, headaches, and dizziness. However, the 2012 Panel did not
believe that seizures and blurred vision were risks associated with
CES, and also suggested that worsening of the condition being treated,
though of concern, could be adequately addressed by a patient being
under the supervision of a medical professional. However, the 2012
Panel consensus was that, given the lack of adequate chronic
effectiveness data, the benefits of the CES device did not outweigh the
risks and the device should remain in class III as use of the device
could present a potential unreasonable risk to health. FDA has
reexamined the available information, however, including information
made available after the 2012 Panel that confirms a level of
effectiveness of CES treatment in certain indications, and believes
that there is evidence of effectiveness for CES usage in treating
patients with insomnia and/or anxiety.
    The available information, while limited, consists of valid
scientific evidence regarding CES use in treating insomnia and anxiety,
which demonstrates basic effectiveness for some indications, as well as
a low risk profile. In terms of safety, there is little evidence of
device risk. FDA's own records (which include real-world clinical
experience) indicate that only a very few adverse events have been
reported over the past 10 years, and those reported have generally been
minor in nature. It is also unclear how many of those events are
attributable to use of the device. In the CES literature, 10 of the
references reviewed reported no adverse events had occurred. Other
studies reported a number of minor adverse events. More common adverse
events reported in the literature include: Blurred vision, headaches,
dizziness, tingling on the forehead, and increased situational anxiety.
There are very limited reports of significant adverse events. In
general, CES devices appear to have a favorable long-term safety
profile. If properly manufactured and used as intended, FDA believes
that the special controls identified in this proposed order, if
finalized, together with general controls (including prescription-use
restrictions and 510(k) notification requirements), are sufficient to
mitigate the risks associated with CES devices intended to treat
insomnia and/or anxiety.
    The effectiveness of CES usage in the conditions studied, insomnia,
depression, and anxiety, is more difficult to determine, as many of the
studies reviewed did not use the Diagnostic and Statistical Manual of
Mental Disorders (DSM) criteria to diagnose insomnia, depression, and
anxiety. Some studies were also limited in terms of sample size,
placebo effect (due to either no masking or unsuccessful masking), and
inadequate statistical methods. Of the 39 papers included in the
literature review presented at the 2012 Panel meeting (Ref. 2), some
reported a beneficial effect of CES on certain indications while others
demonstrated no effect. Furthermore, the body of research reviews 25
different models of CES devices used, excluding 7 that were custom
built, and some studies did not report the CES device model. Because
the electrical output characteristics vary across the different CES
devices, it is difficult to definitively ensure the effectiveness of
any one device. However, the Agency believes that the totality of the
results of these studies do provide information on the general
effectiveness of CES usage for insomnia and/or anxiety.
    FDA's systematic assessment of the published literature, as
presented to the 2012 Panel, included 30 studies for ``on-label'' CES
use (tables 14 and 15 of the FDA Executive Summary) (Ref. 2). Study
design and methodology varied across the published papers, several
different CES devices were evaluated, and the methodology of CES
delivery (e.g., electrode placement, stimulation parameters, duration
and frequency of treatment sessions) also varied.
    There were 24 studies that investigated the impact of CES on
anxiety (11 randomized controlled trials (RCTs), 11 observational
studies, 1 meta-analysis, and 1 systematic review). Of the RCTs that
were evaluated, some trials reported a statistically significant
benefit of CES treatment versus placebo in reducing anxiety symptoms
(Refs. 3 through 8), while other studies demonstrated no difference in
anxiety between the groups (Refs. 9 through 12). Feighner et al. also
conducted an RCT and reported a reduction in anxiety at 15 days after
CES use, but this effect was no longer significant at 26 days (Ref.
13). The majority of observational studies reported a positive
association between CES treatment and reduction in anxiety symptoms
(Refs. 14 through 21). In the single-arm observational study by
Bystritsky et al., improvements were reported for some but not all
measures

of anxiety (Ref. 22). Only two observational studies reported that CES
did not have a significant impact on anxiety based on clinical
assessment and standard inventories (Refs. 23, 24). A meta-analysis of
eight RCTs evaluating the effectiveness of CES on anxiety indicated
that CES versus sham treatment was associated with significantly
improved anxiety (Ref. 25). Similar findings were reported in a
systematic review that examined 34 controlled trials involving a total
of 767 patients receiving CES and an additional 867 patients serving as
controls (Ref. 26). Twenty six of 34 studies (77 percent) reported
decreased anxiety after treatment with CES and the remaining 8 of 34
studies (24 percent) reported no such benefit.
    FDA's assessment identified 18 studies that evaluated the
effectiveness of CES on insomnia. Of the nine RCTs, some reported
statistically significant reductions in insomnia symptoms in the CES
group compared to placebo (Refs. 3, 4, 13, 27), while others reported
no significant differences between the two groups (Refs. 9, 11, 12,
28). A study by Heffernan et al. also reported significant changes
between the active CES treatment and placebo groups (Ref. 8). Among the
eight observational studies, CES treatment was associated with less
frequent (Ref. 15) and less intense (Ref. 18) sleep disturbances, less
difficulty falling asleep (Refs. 29, 30), and feeling more rested in
the morning (Ref. 29). Two observational studies reported no impact of
CES on insomnia (Refs. 31, 32). In a study by Moore et al., subjective
measures of insomnia were markedly improved during the first week of
CES treatment but were no longer significant at 2 weeks (Ref. 23). A
study by Nagata et al reported a significant reduction in sleep latency
in insomniacs but not in those without sleep disorders (Ref. 33).
Lastly, a meta-analysis with pooled results from two RCTs examining the
efficacy of CES for insomnia indicated no difference between the active
CES use and sham groups (Ref. 25).
    While the available scientific literature for insomnia and anxiety
has shortcomings (as described previously) and no individual published
study on CES provides definitive evidence of effectiveness of CES for
the treatment of insomnia and/or anxiety, it is noteworthy that 18 of
the 24 small published studies (those that enrolled fewer than 50
patients) that included assessments of insomnia and/or anxiety had a
main finding that indicated a greater benefit of CES versus control for
at least 1 of the outcome measures evaluated, and CES treatment group
outcomes improved in all large published studies (although not all
studies demonstrated improvement compared with control patients),
including two studies identified after the 2012 Panel meeting (Refs.
34, 35). It is also worth noting that in a report on pain management
(Ref. 36), the Army Surgeon General identifies CES as a potentially
useful device for pain management, and argues that even treatments that
may be associated with a placebo effect should be clinically exploited,
given their effectiveness and safety margin. The report also states
that gaps in evidence for such therapies exist due to lack of funded
research. Based on the available information, it can be concluded that
there is valid scientific evidence of effectiveness for CES in the
treatment of insomnia and/or anxiety. Importantly, however, because
different CES devices were evaluated and the methodology of CES
delivery (e.g., electrode placement, stimulation parameters, duration
and frequency of treatment sessions) varied, the data are insufficient
to determine the technical performance parameters, adequate directions
for use, and warnings for unsafe use for specific devices, and to
determine whether the devices when used in accordance with such
directions will provide clinically meaningful results. Therefore, it
cannot be concluded, based on available information alone, that
specific CES devices will be effective for treating insomnia and/or
anxiety. However, through general and special controls, it can be
demonstrated that specific CES devices will provide clinically
meaningful results.
    FDA believes that these special controls should include clinical
performance data that demonstrates that a device, when used as directed
(including instructions for electrode placement, stimulation
parameters, duration and frequency of treatment sessions, and other
relevant characteristics), will provide clinically meaningful results
in the indicated patient population for the intended use. It should be
noted that the 2012 Panel asked during its meeting whether clinical
data were available as a special control and was told that clinical
data would likely not be collected if CES devices were classified in
class II (Ref. 1). FDA has since reconsidered this point and believes
that the totality of available information demonstrates general
effectiveness of CES usage for insomnia and/or anxiety, but clinical
data are necessary to demonstrate the clinical effect of specific
devices for its labeled intended uses and specific stimulation
parameters.
    Based on its evaluation of the available information, FDA believes
the proposed special controls identified in the next section, including
clinical performance data, and in combination with the general
controls, will provide reasonable assurance of safety and effectiveness
for CES devices in the treatment of insomnia and/or anxiety.

VIII. Proposed Special Controls

    FDA believes that the special controls in Sec.  882.5800(b)(1), in
addition to general controls (including applicable prescription-use
restrictions and 510(k) notification requirements), address the risks
to health and provide reasonable assurance of safety and effectiveness
to mitigate the risks to health described in section V for CES devices
intended to treat insomnia and/or anxiety and provide a reasonable
assurance of safety and effectiveness.
    As discussed in the preceding section, each CES device has
different technological characteristics, and although sufficient
evidence is present to reasonably demonstrate a class effect, a
reasonable assurance of the safety and effectiveness of specific CES
devices from the existing data is not evident based upon differences in
the technological and stimulation parameters for the CES devices.
Therefore, FDA believes that additional clinical performance data are
necessary to support premarket notifications (510(k)s) for these
devices. The intended use population under investigation should
correspond to a clinically recognized diagnosis, or symptomatology
associated with that diagnosis, and sample sizes should provide
adequate statistical power for a reasonable determination of
effectiveness. The output and conditions of use (including electrode
placement) in any clinical investigation used to support the 510(k)
must demonstrate effectiveness for treating insomnia and/or anxiety. In
instances where the device output and/or conditions of use are
different from a predicate, the 510(k) should contain a complete study
report that includes the protocol and clinical study results, including
systematic collection of adverse events. A CES device in compliance
with the special controls could be used as a benchmark. In instances
where the technological and stimulation characteristics are identical,
as identified in the labeling, it may be possible to leverage existing
clinical data in lieu of providing results from a new clinical study.

    A number of comments at the 2012 Panel meeting noted that worsening
of a patient's condition during ineffective treatment is mitigated by
adequate physician monitoring. FDA agrees with this assessment, and we
believe that the labeling must include a warning regarding the need for
physician monitoring. FDA also believes that the clinical data
collected to support a premarket notification will provide additional
information to further characterize this risk and ensure that product
labeling informs the user regarding appropriate use of the device and
the patient population for which the device has sufficient performance
to make a substantial equivalence determination.
    The risks of skin irritation can be mitigated with biocompatibility
testing to ensure that the materials used in patient-contacting
components of the device are safe for skin contact as well as labeling
that provides information on validated methods for reprocessing any
reusable components between uses.
    Headaches due to CES device use are typically transient and this
risk can be mitigated by a warning that advises patients to reduce the
level of stimulation or discontinue use of the device should a headache
occur. The clinical data will also provide evidence regarding the
stimulation parameters recommended for use during the study and the
rate at which headaches occurred; the results and any observed adverse
events must also appear in the labeling.
    Some patients experience a feeling of dizziness at certain levels
of stimulation. FDA believes this risk can be mitigated by a warning
that advises patients to reduce the level of stimulation or discontinue
use of the device if dizziness occurs, and to not drive or operate
heavy machinery while using the device. The clinical data will also
provide evidence regarding the stimulation parameters recommended for
use during the study and the rate at which dizziness occurred; the
results and any observed adverse events must also appear in the
labeling.
    Electrical shocks and burns, including unintended electric
stimulation, pose risk to the patient. FDA believes this risk can be
mitigated through appropriate electrical safety and electromagnetic
compatibility (EMC) testing, and also through appropriate software
verification, validation, and hazard analysis.
    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 CES for Insomnia and
                                 Anxiety
------------------------------------------------------------------------
          Identified risk                    Mitigation measures
------------------------------------------------------------------------
Ineffective treatment.............  Clinical Performance Testing.
                                    Nonclinical (bench) performance
                                     testing.
                                    Characterization and verification of
                                     technical parameters.
                                    Labeling.
Skin irritation...................  Biocompatibility testing.
                                    Labeling.
Headaches.........................  Clinical performance testing.
                                    Labeling.
Dizziness.........................  Clinical performance testing.
                                    Labeling.
Electrical shocks and burns.......  Electrical safety and EMC testing.
                                    Software verification, validation,
                                     and hazard analysis.
------------------------------------------------------------------------

    In addition, under 21 CFR 801.109, the sale, distribution, and use
of these 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. Under Sec.  807.81, the device would continue to be
subject to 510(k) notification requirements.

IX. Dates New Requirements Apply

A. CES Devices Intended To Treat Depression

    In accordance with section 515(b) of the FD&C Act, FDA is proposing
to require that a PMA be filed with the Agency for CES devices intended
to treat depression. Under section 501(f)(2)(B) of the FD&C Act, PMAs
for currently legally marketed CES devices intended to treat depression
are required to be filed on or before 90 days after the effective date
of a final order. However, for currently legally marketed CES devices
intended to treat depression, FDA does not intend to enforce compliance
with this 90-day deadline for an additional 90 days after that deadline
(i.e., 180 days after the effective date of any final order), as long
as notice of intent to file a PMA is submitted within 90 days of the
effective date of the final order. The notification of the intent to
file a PMA submission should include a list of all model numbers for
which a manufacturer plans to seek marketing approval through a PMA.
FDA does not intend to enforce compliance with the PMA requirements
with respect to an applicant of a currently legally marketed CES device
intended to treat depression during FDA's review of the PMA. FDA
intends to review any PMA for the device within 180 days of the date of
filing. FDA cautions that under section 515(d)(1)(B)(i) of the FD&C
Act, the Agency may not enter into an agreement to extend the review
period for a PMA beyond 180 days unless the Agency finds that ``the
continued availability of the device is necessary for the public
health.'' The following table shows the proposed regulatory timetable
for currently legally marketed CES devices intended to treat
depression.

                         Table 2--Timetable for CES Devices Intended To Treat Depression
----------------------------------------------------------------------------------------------------------------
                                            Timetable for which FDA
                                           does not intend to enforce
                                            compliance  (time after    Distribution period (time after effective
                                            effective date of final               date of final order)
                                                     order)
----------------------------------------------------------------------------------------------------------------
Intent to file a PMA....................  90 days....................  Devices included in an intent to file:
                                                                        180 days.

File a PMA..............................  180 days...................  Devices not included in an intent to
                                                                        file: 90 days.
                                                                       Once PMA is filed, FDA does not intend to
                                                                        enforce compliance with PMA requirements
                                                                        until a not approvable decision or
                                                                        denial decision is issued; applicant may
                                                                        continue distribution if an approval
                                                                        order is issued.
----------------------------------------------------------------------------------------------------------------

    FDA intends that under Sec.  812.2(d), the preamble to any final
order based on this proposal will state that, as of the date on which
the filing of a PMA or a notice of completion of a PDP is required to
be filed, the exemptions from the requirements of the IDE regulations
for preamendments class III devices in Sec.  812.2(c)(1) and (2) will
cease to apply to any device that is (1) not legally on the market on
or before that date or (2) legally on the market on or before that date
but for which a PMA or notice of completion of a PDP is not filed by
that date, or for which PMA approval has been denied or withdrawn.
    If a PMA for a class III CES device is not filed with FDA within 90
days after the effective date of any final order requiring premarket
approval for the device, the device would be deemed adulterated under
section 501(f) of the FD&C Act. However, as explained previously, FDA
does not intend to enforce compliance with this 90-day deadline for an
additional 90 days after that deadline (i.e., 180 days after the
effective date of any final order), as long as notice of intent to file
a PMA is submitted within 90 days of the effective date of the final
order.
    The device may be distributed for investigational use only if the
requirements of the IDE regulations are met. The requirements for
significant risk devices include submitting an IDE application to FDA
for its review and approval. An approved IDE is required to be in
effect before an investigation of the device may be initiated or
continued under Sec.  812.30. FDA, therefore, cautions that IDE
applications should be submitted to FDA at least 30 days before the end
of the 90-day period after the effective date of the final order to
avoid interrupting investigations. In conducting any clinical studies,
CES devices intended to treat depression may be distributed for
investigational use if the requirements of the IDE regulations (part
812) are met. There will be no extended period for filing an IDE nor
exemption from IDE requirements, and studies may not be initiated
without appropriate IDE approvals, where necessary.

B. CES Devices Intended To Treat Insomnia and/or Anxiety

    FDA proposes that the special controls identified in this proposed
order take effect on the effective date of any final order, and CES
devices intended to treat insomnia and/or anxiety must comply with the
special controls following the effective date of the final order.
However, FDA does not intend to enforce compliance with the special
controls for currently legally marketed CES devices intended to treat
insomnia and/or anxiety until 1 year after the effective date of the
final order. FDA notes that a firm whose CES device was legally in
commercial distribution before May 28, 1976, or whose device was found
to be substantially equivalent to such a device and who does not intend
to market such device for uses other than use in treating insomnia and/
or anxiety, may remove such intended uses from the device's labeling.
FDA proposes that for those manufacturers who wish to continue to offer
for sale currently legally marketed CES devices intended to treat
insomnia and/or anxiety, the manufacturers submit an amendment to their
previously cleared 510(k)s for the devices within 1 year after the
effective date of the final order that demonstrates compliance with the
special controls. Such amendment will be added to the 510(k) file but
will not serve as a basis for a new substantial equivalence review. A
submitted 510(k) amendment in this context will be used solely to
demonstrate to FDA that a CES device is in compliance with the special
controls. If a 510(k) amendment for the device is not submitted within
1 year of the effective date of the final order or if FDA determines
that the amendment does not demonstrate compliance with the special
controls, then this compliance policy would not apply, and FDA would
intend to enforce compliance with these requirements. In that case, the
device is deemed adulterated under section 501(f)(1)(B) of the FD&C Act
as of the date of FDA's determination of noncompliance or 1 year after
the effective date of the final order, whichever is sooner.
    For models of CES devices intended to treat insomnia and/or anxiety
that have not been legally marketed prior to the effective date of the
final order, or models that have been legally marketed but are subject
to the requirement for a submission of a new 510(k) under Sec.
807.81(a)(3) because the device is about to be significantly changed or
modified, manufacturers must obtain 510(k) clearance, among other
relevant requirements, and demonstrate compliance with the special
controls included in the final order, before marketing the new or
changed device.

X. Proposed Findings With Respect to Risks and Benefits

    As required by section 515(b) of the FD&C Act, FDA is publishing
its proposed findings regarding (1) the degree of risk of illness or
injury designed to be eliminated or reduced by requiring that this
device have an approved PMA or a declared completed PDP when intended
for use in treating depression and (2) the benefits to the public from
the use of CES devices for treating depression.
    These findings are based on the reports and recommendations of the
advisory committees (panels) for the classification of these devices
along with information submitted in response to the FDA Order (74 FR
16214) that was issued under section 515(i) of the FD&C Act and any
additional information that FDA has obtained. Additional information
regarding the risks as well as classification associated with this
device type can be found in 43 FR 55716, 44 FR 51770, 58 FR 45865, and
76 FR 48062.

XI. Device Subject to the Proposal To Require a PMA--CES Devices
Intended To Treat Depression (Sec.  882.5800(c))

A. Identification

    A cranial electrotherapy stimulator is a prescription device that
applies electrical current that is not intended to induce a seizure to
a patient's head to treat depression.

B. Summary of Data

    For treating depression, FDA concludes that the safety and
effectiveness of CES devices have not been established by adequate
scientific evidence. Given the FDA analysis and the advisory panel
deliberations (Ref. 1), there is insufficient evidence of effectiveness
for this indication. The panel recommended class III designation for
CES devices in all indications, although as explained previously, FDA
is proposing to reclassify CES when intended to treat insomnia and/or
anxiety. The body of evidence is not sufficiently robust for FDA to
determine that there is a reasonable assurance of safety and
effectiveness for CES treatment of depression.
    In the Agency's literature assessment, we identified 12 papers that
examined the effect of CES on measures of depression (6 RCTs and 6
observational studies). In most RCTs, depression levels did not differ
significantly between patients who were treated with active CES
compared to those treated with placebo (Refs. 3, 9 through 11, 13),
although one randomized trial by Hearst et al. reported fewer
depression symptoms in the active CES treatment versus placebo groups
(Ref. 12). Of the six observational studies that were reviewed, four
studies reported improvement in depression symptoms after treatment
with CES (Refs. 14, 15, 18, 19). Moore et al. also reported improvement
in depression post- (versus pre-) CES treatment, but the findings were
not statistically significant (Ref. 23). Moreover, the observational
study by Marshall et al. reported no difference in depressive symptoms
between the CES and placebo arms (Ref. 37).
    Among the intended uses of insomnia, anxiety, and depression, the
evidence supporting the effectiveness of CES for treating depression is
the weakest. FDA believes that insufficient information exists
regarding the risks and benefits of the device in order for FDA to
determine that general and/or special controls will provide reasonable
assurance of the safety and effectiveness of CES for treating
depression. As established in section 513(a)(1)(C) of the FD&C Act and
21 CFR 860.3(c)(3), a device is in class III if insufficient
information exists to determine that general controls and/or special
controls are sufficient to provide reasonable assurance of its safety
and effectiveness and the device is purported or represented to be for
a use that is life-supporting or life-sustaining, or for a use which is
of substantial importance in preventing impairment of human health, or
if the device presents a potential unreasonable risk of illness or
injury. FDA believes that the risks to health identified in section V
for the use of CES devices for treating depression, in the absence of
an established positive benefit-risk profile, presents a potential
unreasonable risk of illness or injury.

C. Risks to Health

    The risks to health for CES devices for treatment of depression are
the same as outlined in section V.

D. Benefits of CES Devices

    As discussed previously, there is inadequate scientific evidence
regarding the effectiveness of CES devices for treatment of depression,
although the devices have the potential to benefit the public by
providing an additional treatment option for depression.

XII. PMA Requirements for CES Devices Intended To Treat Depression

    A PMA for CES devices for treatment of depression must include the
information required by section 515(c)(1) of the FD&C Act. Such a PMA
should also include a detailed discussion of the risks identified
previously, as well as a discussion of the effectiveness of the device
for which premarket approval is sought. In addition, a PMA must include
all data and information on: (1) Any risks known, or that should be
reasonably known, to the applicant that have not been identified in
this document; (2) the effectiveness of the device that is the subject
of the application; and (3) full reports of all preclinical and
clinical information from investigations on the safety and
effectiveness of the device for which premarket approval is sought.
    A PMA must include valid scientific evidence to demonstrate
reasonable assurance of the safety and effectiveness of the device for
its intended use (see Sec.  860.7(c)(1)). Valid scientific evidence is
evidence from well-controlled investigations, partially controlled
studies, studies and objective trials without matched controls, well-
documented case histories conducted by qualified experts, and reports
of significant human experience with a marketed device, from which it
can fairly and responsibly be concluded by qualified experts that there
is reasonable assurance of the safety and effectiveness of a device
under its conditions of use. Isolated case reports, random experience,
reports lacking sufficient details to permit scientific evaluation, and
unsubstantiated opinions are not regarded as valid scientific evidence
to show safety or effectiveness. (Sec.  860.7(c)(2)).

XIII. Opportunity To Request a Change in Classification

    Before requiring the filing of a PMA or notice of completion of a
PDP for a device, FDA is required by section 515(b)(2)(D) of the FD&C
Act to provide an opportunity for interested persons to request a
change in the classification of the device based on new information
relevant to the classification. Any proceeding to reclassify the device
will be under the authority of section 513(e) of the FD&C Act.
    A request for a change in the classification of CES devices is to
be in the form of a reclassification petition containing the
information required by Sec.  860.123, including new information
relevant to the classification of the device.

XIV. 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 requires FDA to issue final 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), as
amended by FDASIA, in this proposed order we are proposing to amend
Sec.  882.5800 by (1) revoking the requirements in Sec.  882.5800(b)
and (c) related to the classification of CES devices intended to treat
insomnia and/or anxiety as class III devices and codifying the
reclassification of CES devices intended to treat insomnia and/or
anxiety to class II (special controls); and (2) retaining the
requirements in Sec.  882.5800(b) and (c) related to the classification
of CES devices intended to treat depression as class III devices
subject to PMAs, as described in section XII.

XV. 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.

XVI. 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 21 CFR 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.
    The effect of this order, if finalized, is to shift certain devices
from the 510(k) premarket notification process to the PMA process. To
account for this change, FDA intends to transfer some of the burden
from OMB control number 0910-0120, which is the control number for the
510(k) premarket notification process, to OMB control number 0910-0231,
which is the control number for the PMA process. As noted previously,
FDA estimates that it will receive three new PMAs as a result of this
order, if finalized. Based on FDA's most recent estimates, this will
result in a 1,040-hour burden increase to OMB control number 0910-0231.
FDA also estimates that there will be three fewer 510(k) submissions as
a result of this order, if finalized. Based on FDA's most recent
estimates, this will result in a 136-hour burden decrease to OMB
control number 0910-0120. Therefore, on net, FDA expects a burden hour
increase of 904 hours due to this proposed regulatory change.

XVII. Proposed Effective Date

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

XVIII. Comments for Previous Dockets

    Comments submitted to the previous dockets (2011-N-0504, 2013-N-
0195) have been officially noted and do not need to be resubmitted. FDA
has considered previous docket comments before issuing this proposed
order.

XIX. References

    The following references are on display in the Division of Dockets
Management (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; they are also
available electronically at http://www.regulations.gov. FDA has
verified the Web site addresses, as of the date this document publishes
in the Federal Register, but Web sites are subject to change over time.

1. Transcript, February 10, 2012, meeting of the Neurological
Devices Panel of the Medical Device Advisory Committee, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM335752.pdf.
2. FDA Executive Summary, Prepared for the February 10, 2012,
meeting of the Neurological Devices Panel, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM330887.pdf.
3. Rosenthal, S.H. ``Electrosleep: A Double-Blind Clinical Study.''
Biological Psychiatry 4(2):179-185, 1972.
4. Philip, P., J. Demotes-Mainard, M. Bourgeois, J.D. Vincent,
``Efficiency of Transcranial Electrostimulation on Anxiety and
Insomnia Symptoms During a Washout Period in Depressed Patients. A
Double-Blind Study.'' Biological Psychiatry 29(5):451-456, March 1,
1991.
5. Sousa, A.D., P.C. Choudhury, ``A Psychometric Evaluation of
Electrosleep.'' Indian Journal of Psychiatry 17:133-137, 1975.
6. Gibson, T.H., D.E. O'Hair, ``Cranial Application of Low Level
Transcranial Electrotherapy vs. Relaxation Instruction in Anxious
Patients.'' American Journal of Electromedicine 4(1):18-21, 1987.
7. Ryan, J.J., G.T. Souheaver, ``Effects of Transcerebral
Electrotherapy (electrosleep) on State Anxiety According to
Suggestibility Levels.'' Biological Psychiatry 11(2):233-237, 1976.
8. Heffernan, M., ``The Effect of a Single Cranial Electrotherapy
Stimulation on Multiple Stress Measures.'' The Townsend Letter for
Doctors and Patients 147:60-64, 1995.
9. Levitt, E.A., McI. N. James, P. Flavell, ``A Clinical Trial of
Electrosleep Therapy With a Psychiatric Inpatient Sample.''
Australian and New Zealand Journal of Psychiatry 9(4):287-290, 1975.
10. Passini, F.G., C.G. Watson, J. Herder, ``The Effects of Cerebral
Electric Therapy (electrosleep) on Anxiety, Depression, and
Hostility in Psychiatric Patients.'' Journal of Nervous and Mental
Disease 163(4):263-266, 1976.
11. Scallet, A., R. Cloninger, E. Othmer, The Management of Chronic
Hysteria: A Review and Double-Blind Trial of Electrosleep and Other
Relaxation Methods.'' Diseases of the Nervous System 37(6):347-353,
1976.
12. Hearst, E.D., C.R. Cloninger, E.L. Crews, R.J. Cadoret,
``Electrosleep Therapy: A Double-Blind Trial.'' Archives of General
Psychiatry 30(4):463-466, 1974.
13. Feighner, J.P., S.L. Brown, J.E. Olivier, ``Electrosleep
Therapy: A Controlled Double Blind Study.'' Journal of Nervous and
Mental Disease 157(2):121-128, 1973.
14. Flemenbaum, A., ``Cerebral Electrotherapy (electrosleep): An
Open Clinical Study With a Six Month Follow Up.'' Psychosomatics
15(1):20-24, 1974.
15. Rosenthal, S.H., N.L. Wulfsohn, ``Electrosleep: A Preliminary
Communication.'' Journal of Nervous and Mental Disease 151(2):146-
151, 1970.
16. Ryan, J.J., G.T. Souheaver, ``Role of Sleep in Electrosleep
Therapy for Anxiety.'' Diseases of the Nervous System 38(7):515-517,
1977.
17. Smith, R.B., F.N. Shiromoto, ``The Use of Cranial Electrotherapy
Stimulation to Block Fear Perception in Phobic Patients.'' Current
Therapeutic Research-Clinical and Experimental 51(2):249-253,
February 1992.
18. Matteson, M.T., J.M. Ivancevich, ``An Exploratory Investigation
of CES as an Employee Stress Management Technique.'' Journal of
Health and Human Resource Administration 9:93-109, 1986.
19. Smith, R., ``Cranial Electrotherapy Stimulation in the Treatment
of Stress Related Cognitivie Dysfunction With an Eighteen Month
Follow-up.'' Journal of Cognitive Rehabilitation 17(6):14-18, 1999.
20. Overcash, S.J., A. Siebenthall, ``The Effects of Cranial
Electrotherapy Stimulation and Multisensory Cognitive Therapy on the
Personality and Anxiety Levels of Substance Abuse Patients.''
American Journal of Electromedicine 6(2):105-111, 1989.
21. Rosenthal, S., ``Studies of Electrosleep With Active and
Simulated Treatment.'' The Canadian Journal of Psychiatry/La Revue
canadienne de psychiatrie 12(3):126-130, 1970.
22. Bystritsky, A., L. Kerwin, J. Feusner, ``A Pilot Study of
Cranial Electrotherapy Stimulation for Generalized Anxiety
Disorder.'' Journal of Clinical Psychiatry 69(3):412-417, March
2008.
23. Moore, J.A., C.S. Mellor, K.F. Standage, H. Strong. ``A Double
Blind Study of Electrosleep for Anxiety and Insomnia.'' Biological
Psychiatry 10(1):59-63, 1975.
24. von Richthofen, C.L., C.S. Mellor, ``Electrosleep Therapy: A
Controlled Study of Its Effects in Anxiety Neurosis.'' The Canadian
Journal of Psychiatry/La Revue canadienne de psychiatrie 25(3):213-
219, 1980.
25. Klawansky, S., A. Yeung, C. Berkey, N. Shah, ``Meta-Analysis of
Randomized Controlled Trials of Cranial Electrostimulation: Efficacy
in Treating Selected Psychological and Physiological Conditions.''
Journal of Nervous and Mental Disease 183(7):478-484, 1995.
26. De Felice, E.A., ``Cranial Electrotherapy Stimulation (CES) in
the Treatment of Anxiety and Other Stress-Related Disorders: A
Review of Controlled Clinical Trials.'' Stress Medicine 13(1):31-42,
1997.

27. Weiss, M., ``The Treatment of Insomnia Through the Use of
Electrosleep: An EEG Study.'' Journal of Nervous and Mental Disease
157(2):108-120, 1973.
28. Coursey, R.D., B.L. Frankel, K.R. Gaarder, D.E. Mott, ``A
Comparison of Relaxation Techniques With Electrosleep Therapy for
Chronic, Sleep-Onset Insomnia: A Sleep-EEG Study.'' Biofeedback and
Self-Regulation 5(1):57-73, 1980.
29. Cartwright, R.D., M.F. Weiss, ``The Effects of Electrosleep on
Insomnia Revisited.'' Journal of Nervous and Mental Disease
161(2):134-137, 1975.
30. Itil, T., P. Gannon, S. Akpinar, W. Hsu, ``Quantitative EEG
Analysis of Electrosleep Using Analog Frequency Analyzer and Digital
Computer Methods.'' Diseases of the Nervous System 33(6):376-381,
1972.
31. Empson, J.A., ``Does Electrosleep Induce Natural Sleep?''
Electroencephalography and Clinical Neurophysiology 35(6):663-664,
1973.
32. Frankel, B.L., R. Buchbinder, F. Snyder, ``Ineffectiveness of
Electrosleep in Chronic Primary Insomnia.'' Archives of General
Psychiatry 29(4):563-568, 1973.
33. Nagata, K., Y. Morita, H. Seno, J. Matsumoto, ``Studies of
Electrosleep on Normal Adults, Insomniacs, and Hypertensive
Patients.'' Tokushima Journal of Experimental Medicine 28(3-4):69-
83, 1981.
34. Lande, R.G., C. Gragnani, ``Efficacy of Cranial Electric
Stimulation for the Treatment of Insomnia: A Randomized Pilot
Study.'' Complementary Therapies in Medicine 21:8-13, 2013.
35. Barclay, T.H., R.D. Barclay, ``A Clinical Trial of Cranial
Electrotherapy Stimulation for Anxiety and Comorbid Depression.''
Journal of Affective Disorders 164:171-177, 2014.
36. Pain Management Task Force, Final Report, May 2010. Office of
The Army Surgeon General.
37. Marshall, A.G., C.E. Izard, ``Cerebral Electrotherapeutic
Treatment of Depressions.'' Journal of Consulting and Clinical
Psychology 42(1):93-97, 1974.

List of Subjects in 21 CFR Part 882

    Medical devices, Neurological 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 882 be amended as follows:

PART 882--NEUROLOGICAL DEVICES

0
1. The authority citation for 21 CFR part 882 continues to read as
follows:

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

0
2. Revise Sec.  882.5800 to read as follows:

Sec.  882.5800  Cranial electrotherapy stimulator.

    (a) Identification. A cranial electrotherapy stimulator is a
prescription device that applies electrical current that is not
intended to induce a seizure to a patient's head to treat psychiatric
conditions.
    (b) Classification. (1) Class II (special controls) when intended
to treat insomnia and/or anxiety. The special controls for this device
are:
    (i) A detailed summary of the clinical testing pertinent to use of
the device to demonstrate the effectiveness of the device when intended
to treat insomnia and/or anxiety.
    (ii) Components of the device that come into human contact must be
demonstrated to be biocompatible.
    (iii) The device must be designed and tested for electrical safety
and electromagnetic compatibility (EMC) in its intended use
environment.
    (iv) Appropriate software verification, validation, and hazard
analysis must be performed.
    (v) The technical parameters of the device, including waveform,
output mode, pulse duration, frequency, train delivery, maximum charge
and energy, must be fully characterized and verified.
    (vi) The labeling for the device must include the following:
    (A) The intended use population and the intended use environment.
    (B) A warning that patients should be monitored by their physician
for signs of worsening.
    (C) A warning that instructs patients on how to mitigate the risk
of headaches, and what to do should a headache occur.
    (D) A warning that instructs patients on how to mitigate the risk
of dizziness, and what to do should dizziness occur.
    (E) A detailed summary of the clinical testing, which includes the
clinical outcomes associated with the use of the device, and a summary
of adverse events and complications that occurred with the device.
    (F) Instructions for use that address where to place the
electrodes, what stimulation parameters to use, and duration and
frequency of treatment sessions. This information must be based on the
results of clinical studies for the device.
    (G) A detailed summary of the device technical parameters,
including waveform, output mode, pulse duration, frequency, train
delivery, and maximum charge and energy.
    (H) Information on validated methods for reprocessing any reusable
components between uses.
    (vii) Cranial electrotherapy stimulator devices marketed prior to
the effective date of this reclassification must have an amendment
submitted to the previously cleared premarket notification (510(k))
demonstrating compliance with these special controls.
    (2) Class III (premarket approval) when intended to treat
depression.
    (c) Date premarket approval application (PMA) or notice of
completion of product development protocol (PDP) is required. A PMA or
notice of completion of a PDP is required to be filed with the Food and
Drug Administration on or before [A DATE WILL BE ADDED 90 DAYS AFTER
DATE OF PUBLICATION OF A FUTURE FINAL ORDER IN THE FEDERAL REGISTER],
for any cranial electrotherapy stimulator device with an intended use
described in (b)(3) of this section, that was in commercial
distribution before May 28, 1976, or that has, on or before [A DATE
WILL BE ADDED 90 DAYS AFTER DATE OF PUBLICATION OF A FUTURE FINAL ORDER
IN THE FEDERAL REGISTER], been found to be substantially equivalent to
any cranial electrotherapy stimulator device with an intended use
described in paragraph (b)(3) of this section, that was in commercial
distribution before May 28, 1976. Any other cranial electrotherapy
stimulator device with an intended use described in paragraph (b)(3) of
this section shall have an approved PMA or declared completed PDP in
effect before being placed in commercial distribution.

    Dated: January 15, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-01173 Filed 1-21-16; 8:45 am]
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[Federal Register: June 29, 2009 (Volume 74, Number 123)]
[Notices]
[Page 31040]
[DOCID:fr29jn09-68]

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DEPARTMENT OF HOMELAND SECURITY

Federal Emergency Management Agency

[Internal Agency Docket No. FEMA-1845-DR; Docket ID FEMA-2008-0018]

Arkansas; Major Disaster and Related Determinations

AGENCY: Federal Emergency Management Agency, DHS.

ACTION: Notice.

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

SUMMARY: This is a notice of the Presidential declaration of a major
disaster for the State of Arkansas (FEMA-1845-DR), dated June 16, 2009,
and related determinations.

DATES: Effective Date: June 16, 2009.

FOR FURTHER INFORMATION CONTACT: Peggy Miller, Disaster Assistance
Directorate, Federal Emergency Management Agency, 500 C Street, SW.,
Washington, DC 20472,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION: Notice is hereby given that, in a letter
dated June 16, 2009, the President issued a major disaster declaration
under the authority of the Robert T. Stafford Disaster Relief and
Emergency Assistance Act, 42 U.S.C. 5121 et seq. (the ``Stafford
Act''), as follows:

    I have determined that the damage in certain areas of the State
of Arkansas resulting from severe storms, tornadoes, and flooding
beginning on April 27, 2009, and continuing, is of sufficient
severity and magnitude to warrant a major disaster declaration under
the Robert T. Stafford Disaster Relief and Emergency Assistance Act,
42 U.S.C. 5121 et seq. (the ``Stafford Act''). Therefore, I declare
that such a major disaster exists in the State of Arkansas.
    In order to provide Federal assistance, you are hereby
authorized to allocate from funds available for these purposes such
amounts as you find necessary for Federal disaster assistance and
administrative expenses.
    You are authorized to provide Public Assistance in the
designated areas, Hazard Mitigation throughout the State, and any
other forms of assistance under the Stafford Act that you deem
appropriate. Direct Federal assistance is authorized. Consistent
with the requirement that Federal assistance is supplemental, any
Federal funds provided under the Stafford Act for Public Assistance
and Hazard Mitigation will be limited to 75 percent of the total
eligible costs. If Other Needs Assistance under Section 408 of the
Stafford Act is later requested and warranted, Federal funding under
that program will also be limited to 75 percent of the total
eligible costs.
    Further, you are authorized to make changes to this declaration
to the extent allowable under the Stafford Act.

    The Federal Emergency Management Agency (FEMA) hereby gives notice
that pursuant to the authority vested in the Administrator, under
Executive Order 12148, as amended, Gerard M. Stolar, of FEMA is
appointed to act as the Federal Coordinating Officer for this major
disaster.
    The following areas of the State of Arkansas have been designated
as adversely affected by this major disaster:

    Arkansas, Bradley, Calhoun, Chicot, Clark, Cleveland, Conway,
Dallas, Drew, Fulton, Grant, Greene, Hempstead, Hot Spring, Howard,
Jackson, Jefferson, Lafayette, Lee, Lincoln, Little River, Marion,
Miller, Monroe, Nevada, Ouachita, Perry, Phillips, Pike, Poinsett,
Polk, Prairie, Saint Francis, Saline, Searcy, Stone, and Union
Counties for Public Assistance. Direct Federal Assistance is
authorized.
    All counties within the State of Arkansas are eligible to apply
for assistance under the Hazard Mitigation Grant 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. E9-15360 Filed 6-26-09; 8:45 am]

BILLING CODE 9111-23-P