Document ID: FDA-2014-N-1209-0001
Agency: fda
Document Type: Proposed Rule
Title: 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
Posted Date: 2016-01-22T05:00Z

[Federal Register Volume 81, Number 14 (Friday, January 22, 2016)]
[Proposed Rules]
[Pages 3751-3762]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[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.''

[[Page 3752]]

    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, 301-796-6283, 
michael.ryan@fda.hhs.gov.

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).)

[[Page 3753]]

    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.

[[Page 3754]]

    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.

[[Page 3755]]

    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,

[[Page 3756]]

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

[[Page 3757]]

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.

[[Page 3758]]

    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.

[[Page 3759]]

 
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.

[[Page 3760]]

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.

[[Page 3761]]

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.

[[Page 3762]]

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]
 BILLING CODE 4164-01-P