[Federal Register Volume 84, Number 245 (Friday, December 20, 2019)]
[Rules and Regulations]
[Pages 70003-70013]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2019-27295]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Final amendment; final order.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final 
order to reclassify the cranial electrotherapy stimulator (CES) device 
intended to treat anxiety and/or insomnia, a preamendments class III 
device, into class II (special controls) and subject to premarket 
notification. FDA is also issuing this final order to require the 
filing of a premarket approval application (PMA) or a notice of 
completion of a product development protocol (PDP) for CES devices 
intended to treat depression (product code JXK) and clarify the device 
identification of the CES device to include it as a prescription 
device.

DATES: This order is effective on December 20, 2019. See further 
discussion in section V, ``Implementation Strategy.''

FOR FURTHER INFORMATION CONTACT: Michael Hoffmann, Center for Devices 
and Radiological Health, 10903 New Hampshire Ave., Bldg. 66, Silver 
Spring, MD 20993, 301-796-6610, [email protected].

SUPPLEMENTARY INFORMATION: 

Table of Contents

I. Table of Abbreviations/Commonly Used Acronyms in This Document
II. Background
    A. Reclassification
    B. Requirement for Premarket Approval
    C. Valid Scientific Evidence
III. Public Comments in Response to the Proposed Order
IV. The Final Order
V. Implementation Strategy
    A. Date To File a PMA
    B. Compliance With Special Controls
VI. Codification of Orders
VII. Analysis of Environmental Impact
VIII. Paperwork Reduction Act of 1995
IX. References

I. Table of Abbreviations/Commonly Used Acronyms in This Document

------------------------------------------------------------------------
      Abbreviation or acronym                   What it means
------------------------------------------------------------------------
2012 Panel........................  2012 Neurological Devices Panel.
510(k)............................  Premarket Notification.
AC................................  Alternating Current.
CES...............................  Cranial Electrotherapy Stimulator
                                     Device.
CFR...............................  Code of Federal Regulations.
CNS...............................  Central Nervous System.
DC................................  Direct Current.
DSM-5.............................  Diagnostic and Statistical Manual of
                                     Mental Disorders, Fifth Edition.
ECT...............................  Electroconvulsive Therapy Device.
FDA...............................  Food and Drug Administration.
FDASIA............................  Food and Drug Administration Safety
                                     and Innovation Act.
FD&C Act..........................  Federal Food, Drug, and Cosmetic
                                     Act.
FR................................  Federal Register.
IDE...............................  Investigational Device Exemption.
MAUDE.............................  Manufacturer and User Facility
                                     Device Experience.
MDR...............................  Medical Device Reporting.
OMB...............................  Office of Management and Budget.
PDP...............................  Product Development Protocol.
PMA...............................  Premarket Approval Application.
PRA...............................  Paperwork Reduction Act of 1995.
RCT...............................  Randomized Controlled Trial.
Ref...............................  Reference.
RWD...............................  Real-World Data.
RWE...............................  Real-World Evidence.
U.S.C.............................  United States Code.
VSE...............................  Valid Scientific Evidence.
------------------------------------------------------------------------

II. Background

    The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended, 
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

[[Page 70004]]

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 
classification regulation classifying the device; and (3) published a 
final classification 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.\1\ 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).
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    \1\ CES devices with intended uses outside the scope of those 
listed in 21 CFR 882.5800 are considered postamendments devices that 
are subject to classification under section 513(f)(1) of the FD&C 
Act or, if the relevant requirements are met, under section 
513(f)(2) of the FD&C Act.
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    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.

A. Reclassification

    Under section 515(i)(2) of the FD&C Act, following publication of a 
proposed order, a meeting of a device classification panel, and 
consideration of the comments of a proposed order, FDA has the 
authority to issue an administrative order revising the classification 
of a device that FDA has classified as a class III device and for which 
no administrative order has been issued calling for PMAs under section 
515(b) of the FD&C Act, so that the device is classified into class I 
or II. In determining whether to revise the classification of a device 
or to require a device to remain in class III, FDA applies the criteria 
set forth in section 513(a) of the FD&C Act. Section 513(a)(1)(B) of 
the FD&C Act defines class II devices as those devices for which the 
general controls in section 513(a)(1)(A) by themselves are insufficient 
to provide reasonable assurance of safety and effectiveness, but for 
which there is sufficient information to establish special controls 
that, together with general controls, provide a reasonable assurance of 
safety and effectiveness of a device.
    FDA published a proposed order in the Federal Register of January 
22, 2016 (81 FR 3751) and held a meeting of the Neurological Devices 
Panel for a discussion of the CES device classification on February 10, 
2012 (the 2012 Panel), as described in section 513(b) of the FD&C Act 
with respect to CES devices (Ref. 1). FDA also published an order in 
the Federal Register of September 10, 2009 (74 FR 16214), that was 
issued under section 515(i) of the FD&C Act that required submission of 
safety and effectiveness information on CES devices. FDA has considered 
the information available to the Agency, including the deliberations of 
the 2012 Panel meeting, the reclassification petitions submitted for 
these devices, and comments from the public docket to determine that 
there is sufficient information to establish special controls to 
effectively mitigate the risks to health identified in section III, 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 anxiety and/or insomnia.
    Therefore, in accordance with sections 513(e)(1) and 515(i) of the 
FD&C Act, based on information with respect to the CES device and 
taking into account the public health benefit of the use of the CES 
device and the nature and known incidence of the risk of the device, 
FDA, on its own initiative, is issuing this final order to reclassify 
CES devices intended for treatment of anxiety and/or insomnia from 
class III to class II (special controls).\2\
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    \2\ FDA notes that the ``ACTION'' caption for this final order 
is styled as ``Final amendment; final order,'' rather than ``Final 
order.'' Beginning in December 2019, this editorial change was made 
to indicate that the document ``amends'' the Code of Federal 
Regulations. The change was made in accordance with the Office of 
Federal Register's (OFR) interpretations of the Federal Register Act 
(44 U.S.C. chapter 15), its implementing regulations (1 CFR 5.9 and 
parts 21 and 22), and the Document Drafting Handbook.
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B. Requirement for Premarket Approval

    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, payers, and providers. As noted 
above, FDA published a proposed order that would require PMAs for CES 
devices intended to treat depression in the Federal Register of January 
22, 2016. FDA held a meeting of a device classification panel described 
in section 513(b) of the FD&C Act with respect to CES devices (Ref. 2). 
Finally, FDA received and considered over 300 comments on the proposed 
order, as discussed in section III. Therefore, FDA has met the 
requirements under section 515(b)(1) of the FD&C Act.
    On July 9, 2012, the Food and Drug Administration Safety and 
Innovation Act (FDASIA) (Pub. L. 112-144) was enacted. Section 608(a) 
and (b) of FDASIA amended sections 513(e) and 515(b) of the FD&C Act, 
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 device from rulemaking to an 
administrative order. In the Federal Register of December 17, 2018 (83 
FR 64443), FDA published a final rule entitled ``Medical Device 
Classification Procedures: Incorporating Food and Drug Administration 
Safety and Innovation Act Procedures,'' which codified those sections 
of FDASIA (Medical Device Classification Procedures Final Rule).
    Although under the FD&C Act a manufacturer of a class III 
preamendments device may respond to the call for PMAs by filing a PMA 
or a notice of completion of a PDP, in practice, the option of filing a 
notice of completion of a PDP has not been used. While corresponding 
requirements for PDPs remain available to manufacturers in response to 
a final order under section 515(b) of the FD&C Act, for simplicity this 
document will refer only to the requirement for the filing and 
receiving approval of a PMA.
    Under section 501(f)(2)(B) of the FD&C Act (21 U.S.C. 
351(f)(2)(B)), a preamendments class III device may be commercially 
distributed without a PMA until 90 days after FDA issues a

[[Page 70005]]

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. Because CES devices 
that are the subject of this final order were classified in 1979 (44 FR 
51770, September 4, 1979), the 30-month period has expired and, thus, 
the later of these two time periods is the 90-day period. However, for 
currently legally marketed CES devices intended to treat depression, 
FDA does not intend to enforce compliance with this 90-day requirement 
for an additional 90 days (i.e., 180 days after the effective date of 
this final order), as long as a notice of intent to file a PMA is 
submitted within 90 days of the effective date of this final order. The 
notification of the intent to file a PMA 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.''
    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 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 and it has been determined that the device is a ``significant 
risk'' under Sec.  812.3(m). If the manufacturer, importer, or other 
sponsor 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 within 90 days after the issuance of a 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. As stated above, FDA does not intend to enforce the 
requirement that a PMA be filed or that it has an approved IDE, if 
applicable, within 90 days, if a notice of intent to file a PMA is 
filed within 90 days of the effective date of this order. 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). FDA 
requests that manufacturers take action to prevent the further use of 
devices for which no PMA has been filed.

C. Valid Scientific Evidence

    The evidentiary standard FDA relies on to determine the safety and 
effectiveness of a device is valid scientific evidence. Section 
860.7(c)(2) (21 CFR 860.7(c)(2)) defines valid scientific evidence. As 
described in section III, in finalizing this order, FDA has assessed 
the totality of the valid scientific evidence available to FDA. This 
evidence includes the literature discussed in the proposed order and 
the information provided in response to the proposed order, including 
several comments that referenced additional clinical studies. FDA also 
considered randomized controlled clinical studies, single arm studies, 
and systematic literature reviews that were submitted in the comments. 
Single case reports or opinion-based commentary were also submitted to 
the dockets for consideration; however, without well controlled 
empirical experimentation, these types of information are generally not 
considered valid scientific evidence and were not relied upon to 
support this reclassification.
    Section 860.7(c)(2) also explains that although random experience 
and reports lacking sufficient details to permit scientific evaluation 
are not regarded as valid scientific evidence to show safety or 
effectiveness, such information may be considered in identifying a 
device, the safety and effectiveness of which is questionable (Sec.  
860.7(c)(2)). Such random experience and reports lacking sufficient 
details to permit scientific evaluation may be early and, sometimes, 
informal indications that the device is unsafe and/or ineffective (43 
FR 32988 at 32990, July 28, 1978). Where FDA is considering the 
classification of a device, such random experience and reports are not 
considered valid scientific evidence (Sec.  860.7(c)(2)).
    FDA received many comments from healthcare professionals describing 
their practices, the length of time they have been practicing, and the 
utilization of CES devices in treating patients with certain 
conditions. While FDA acknowledges receiving comments in providing 
information for recommending the reclassification of CES devices for 
treatment of certain conditions including anxiety, insomnia, and 
depression, statements by individual healthcare professionals that they 
have used CES devices to treat individual patients do not constitute 
valid scientific evidence to demonstrate reasonable assurance of safety 
and effectiveness (see Valid Scientific Evidence (VSE) discussion in 48 
FR 56778 at 56787-56788, comments 16-21, December 23, 1983 (Ref. 3)). 
Such comments do not contain sufficient detail to capture the use of 
the device, exposures, and outcomes in the appropriate population and 
are not interpretable using informed clinical and scientific judgment.
    FDA also received many comments from patients, or friends and 
family of patients, in support of and against reclassification of CES 
devices for specific indications for use. These comments described the 
experience of the patient that received treatment from a CES device. 
FDA acknowledges receiving comments from patients and other individuals 
about their positive experiences with CES devices being considered for 
reclassification; however, FDA does not consider such comments to be 
valid scientific evidence. Because these comments did not contain 
sufficient data sources to capture the use of the device, exposures, 
and outcomes in the appropriate population and are not interpretable 
using informed clinical and scientific judgment, such comments are not 
considered valid scientific evidence.
    For medical devices, available evidence traditionally consists of 
clinical and non-clinical studies conducted and provided to FDA by the 
device manufacturer or sponsor. However, FDA recognizes that a wealth 
of data covering medical device experience is routinely collected in 
the course of treatment and management of patients. Under certain 
circumstances, these real-world data (RWD) may constitute real-world 
evidence (RWE), or clinical evidence regarding the usage and potential 
benefits or risks of a medical product derived from analysis of RWD, 
that may be of sufficient quality to help inform or augment FDA's 
understanding of the benefit-risk profile of devices at various points 
in their life cycle, and could potentially be valid scientific evidence 
used to aid FDA in regulatory decision making. See FDA's

[[Page 70006]]

guidance, ``Use of Real-World Evidence to Support Regulatory Decision-
Making for Medical Devices'' (82 FR 41418, August 31, 2017) (Ref. 4), 
which clarifies how FDA evaluates RWD to determine whether it may be 
sufficiently relevant and reliable to generate the types of RWE that 
can be used in FDA regulatory decision making for medical devices, 
including potentially generating valid scientific evidence.
    In order to determine the suitability of RWD for regulatory 
decision making, FDA will assess the relevance and reliability of the 
source and its specific elements. This assessment will be used to 
determine whether the RWD source(s) and the proposed analysis can 
generate evidence that is sufficiently robust to be used for a given 
regulatory purpose. Whether evidence is sufficiently relevant and 
reliable for use will, in part, depend on the level of quality 
necessary to make a particular regulatory decision (Ref. 4). Although 
FDA received numerous comments to the proposed order of patient and 
healthcare professionals' experiences with CES devices, many of the 
comments did not include sufficient data sources as evidence for 
consideration of reclassification of CES devices intended for treatment 
of depression in finalizing this order.

III. Public Comments in Response to the Proposed Order

    On January 22, 2016, FDA published in the Federal Register a 
proposed order to reclassify from class III to class II, subject to 
premarket notification, the CES devices intended to treat anxiety and/
or insomnia and to require filing of a PMA for CES devices intended to 
treat depression. The comment period on the proposed order closed on 
April 21, 2016.
    In response to the January 22, 2016, proposed order, FDA received 
over 300 comments from industry, professional societies, trade 
organizations, and individual consumers by the close of the comment 
period, each containing one or more comments on one or more issues.
    We describe and respond to the comments in this section of the 
document. The comments are grouped based on common themes; we grouped 
similar comments together under the same number and listed them 
numerically. The number assigned to each group is purely for 
organizational purposes and does not signify the comment's value or 
importance or the order in which comments were received. Please note 
that in some cases we separated different issues discussed by the same 
commenter and designated them as distinct comments for purposes of our 
responses.
    (Comment 1) FDA received numerous comments in favor of the proposed 
reclassification of CES for treatment of anxiety and/or insomnia into 
class II with special controls.
    (Response 1) Based on the consideration of the deliberation at the 
2012 Panel meeting, valid scientific evidence, and review of relevant 
scientific articles and comments received in response to the 2016 
proposed order, FDA continues to believe that CES devices intended to 
treat anxiety and/or insomnia should be reclassified from class III to 
class II (Refs. 1, 5, and 6), as initially specified in the proposed 
order. FDA has made this determination based upon an assessment (or, in 
some cases, reassessment) of the following sources of information: (1) 
Published literature referenced in the Executive Summary to the 2012 
Panel; (2) comments and literature received in public dockets including 
the call for safety and effectiveness information for all preamendments 
class III devices (74 FR 16214), the 2012 Panel (76 FR 6625, February 
7, 2011), and the proposed order (81 FR 3751); and (3) review of 
medical device reports (MDRs) in the FDA Manufacturer and User Facility 
Device Experience (MAUDE) database. The reevaluation of the scientific 
evidence presented to and discussed at the 2012 Panel meeting, and the 
review of additional post-2012 scientific information, further supports 
this finding. Based on the totality of this available evidence, FDA has 
determined that the designated special controls, together with general 
controls, mitigate the risks to health associated with use of CES for 
the specific indications of treating anxiety and/or insomnia and 
provide a reasonable assurance of safety and effectiveness, as 
initially specified in the proposed order. Table 1 identifies the risks 
associated with CES for treatment of anxiety and/or insomnia and the 
necessary mitigation measures by the required special controls. In this 
final order, FDA has included a non-substantive, clarifying edit in 
table 1 for the mitigation measures for skin irritation by changing 
``biocompatibility testing'' to ``biocompatibility evaluation'' in 
table 1. As a result, FDA is adopting the special controls identified 
in the proposed order for CES devices for the treatment of anxiety and/
or insomnia. Therefore, FDA has determined that the proposed special 
controls identified in this final order, in combination with general 
controls, provide a reasonable assurance of safety and effectiveness of 
CES for treatment of anxiety and/or insomnia.
    FDA will also create a new product code for CES devices intended 
for the treatment of anxiety and/or insomnia.

     Table 1--Identified Risks to Health and Mitigation Measures for
           Treatment of Anxiety and/or Insomnia in CES Devices
------------------------------------------------------------------------
            Identified risk                    Mitigation measures
------------------------------------------------------------------------
Ineffective treatment..................  Clinical Performance Testing.
                                         Non-clinical (bench)
                                          performance testing.
                                         Characterization and
                                          Verification of technical
                                          Parameters.
                                         Labeling.
Skin irritation........................  Biocompatibility Evaluation
                                          Labeling.
Headaches..............................  Clinical Performance Testing
                                          Labeling.
Dizziness..............................  Clinical Performance Testing
                                          Labeling.
Electrical shocks and burns............  Electrical safety and
                                          electromagnetic compatibility
                                          testing.
                                         Software verification,
                                          validation and hazard
                                          analysis.
------------------------------------------------------------------------

    (Comment 2) Several comments opposed maintaining the classification 
of CES for the treatment of depression in class III and the call for 
PMAs for the following reasons: (1) There are little to no safety or 
effectiveness concerns; (2) maintaining the classification of CES for 
treatment of depression as class III is inconsistent with the statutory 
definition of class III because, among other things, it does not 
``present a potential unreasonable risk of illness or

[[Page 70007]]

injury'' based on valid scientific evidence available at the time of 
premarket clearance; (3) CES for treatment of depression may be 
addressed by requiring clinical performance data to support a premarket 
notification (510(k)); and (4) there is prevalence of comorbidity of 
anxiety disorders and depression that supports the reclassification of 
CES for treatment of depression to class II.
    (Response 2) Based on the totality of evidence, including 
consideration of the deliberation at the 2012 Panel meeting, recent 
review of relevant scientific articles, and comments received in 
response to the 2016 proposed order (81 FR 3751), FDA continues to 
disagree with reclassification of CES for treatment of depression into 
class II. FDA has identified the following reasons for maintaining CES 
for the treatment of depression in class III and the call for PMAs:
    (Response 2A) FDA disagrees that there are no safety or 
effectiveness concerns with reclassifying CES devices for treatment of 
depression into class II. As noted previously, the evidentiary standard 
FDA relies on to determine the safety and effectiveness of a device is 
valid scientific evidence as defined in Sec.  860.7(c)(2). In 
finalizing this order, FDA has assessed the totality of the valid 
scientific evidence for treatment of depression that was discussed at 
the 2012 Panel meeting and provided in comments to the 2016 proposed 
order, including several comments that referenced additional clinical 
studies. In addition, this assessment also included an updated analysis 
of the publicly available safety data in FDA's MAUDE database and an 
updated review of the literature.
    For the treatment of depression, FDA concluded in the 2016 proposed 
order that there was insufficient information to establish special 
controls that, in addition to general controls, would provide 
reasonable assurance of safety and effectiveness of CES devices for 
treating depression (81 FR 3751 at 3760).
    The Agency's previous literature assessment identified 12 papers 
that examined the effect of CES on measures of depression (6 Randomized 
Controlled Trials (RCT) 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. 7-11), 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. 13-16). Moore et al. also reported 
improvement in depression post- (versus pre-) CES treatment, but the 
findings were not statistically significant (Ref. 17). The 
observational study by Marshall et al. reported no difference in 
depressive symptoms between the CES and placebo arms (Ref. 18). 
Moreover, the observational study Marshall et al. reported no 
difference in depressive symptoms between the CES and placebo arms 
(Ref. 18).
    Among the intended uses of insomnia, anxiety, and depression, the 
evidence supporting the effectiveness of CES for treating depression 
was the weakest. As established in section 513(a)(1)(C) of the FD&C Act 
and Sec.  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 earlier in 
this section, 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. FDA therefore 
concluded that there was insufficient information regarding the risks 
and benefits of the device for FDA to establish special controls that, 
in combination with general controls, would provide reasonable 
assurance of the safety and effectiveness of CES for treating 
depression.
    As of the date of this final order, there is still insufficient 
information to establish special controls that, in addition to general 
controls, will provide reasonable assurance of safety and effectiveness 
of CES devices for treating depression. FDA has reviewed all the 
scientific literature that was cited in comments submitted to the 
docket of the 2016 proposed order. While these articles had not been 
discussed specifically in the proposed order, FDA is clarifying that 
they are not-supportive to the reclassification of CES for treatment of 
depression. Specifically, these articles have significant shortcomings, 
such as lacking a well-controlled design (Ref. 19), lacking a diagnosis 
for eligibility (Ref. 20), having uncertain correlation with diagnostic 
criteria used in the United States (Ref. 21), containing an exclusion 
for unipolar depression (Ref. 22), lacking an appropriately matched 
control group (Ref. 23), and/or including studies that did not focus 
specifically on CES (Refs. 24 and 25). In one case, while FDA 
considered a reference supportive of reclassification for anxiety, 
there was insufficient information to support reclassification for 
depression because the two groups were not matched with respect to the 
diagnosis (Ref. 26). Thus, these articles do not justify FDA changing 
the classification of CES devices intended for treatment of depression. 
Following the closure of the comment period for the 2016 proposed 
order, as part of the assessment of the current state of scientific 
evidence for CES devices, FDA also conducted an updated review of 
scientific literature. The search used a similar methodology as 
previous searches conducted in support of the preceding Federal 
Register orders, and the 2012 Panel meeting. As part of FDA's 
systematic identification of literature, FDA did not identify studies 
regarding the use of CES to treat depression as the primary diagnosis. 
However, FDA did identify four studies either where symptoms of 
depression were studied in populations of subjects where the primary 
diagnosis was not a psychiatric condition (Refs. 27 to 29), or where 
there was one single session administered to examine acute 
physiological changes only (Ref. 30). FDA evaluated these studies to 
determine whether they were designed to assess the use of CES to treat 
depressive disorders that are recognized by the clinical community as 
identified in the Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition (DSM-5, published 2013) (Ref. 31). FDA 
concluded that the four studies published after January 1, 2016, 
through November 1, 2019, did not contribute sufficient information in 
the form of valid scientific evidence to demonstrate that the subjects 
met the criteria for any recognized depressive disorder, as defined in 
DSM-5 (Ref. 31).
    In addition, FDA conducted a review of adverse event reporting for 
CES devices since the publication of the proposed order. The FDA's 
MAUDE database search resulted in a total of three additional CES-
related medical device reporting (MDRs) and one possibly pertinent to 
CES between January 1, 2016, and September 1, 2019. Two MDRs were 
injury reports submitted by voluntary reporters for a CES device 
manufacturer. A third MDR was a malfunction report submitted by a 
device manufacturer for an implanted intestinal stimulator and noted 
concomitant use of an unspecified CES

[[Page 70008]]

device and a fourth MDR report was used to ``improve brain 
functioning'' with a report of a third-degree burn. Although there are 
a low number of MDRs related to CES devices, the adverse reports for 
treatment of depression are only one factor (e.g., other factors may 
include the patient population targeted, alternative therapies) for FDA 
to consider in concluding that there is insufficient information to 
establish special controls that, in combination with general controls, 
will provide a reasonable assurance of safety and effectiveness of CES 
for the treatment of depression. FDA continues to believe that the 
risks to health identified 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. 
Thus, following the review of all the evidence presented, FDA has 
concluded that there is insufficient evidence to establish special 
controls that, in addition to general controls, will provide a 
reasonable assurance of safety and effectiveness for CES in treating 
depression. Accordingly, it is appropriate to maintain CES for 
treatment of depression in class III.
    (Response 2B) FDA disagrees that maintaining the classification of 
CES for treatment of depression in class III is inconsistent with the 
statutory definition of class III. Section 513(a)(1)(C) of the FD&C Act 
(21 U.S.C. 360c(a)(l)(C)) defines class III, premarket approval as the 
following:

    (1) A device which because it cannot be classified as a class I 
device because insufficient information exists to determine that the 
application of general controls are sufficient to provide reasonable 
assurance of the safety and effectiveness of the device, (2) cannot 
be classified as a class II device because insufficient information 
exists to determine that the special controls described in 
subparagraph (B) would provide a reasonable assurance of its safety 
and effectiveness, and is purported or represented to be for a use 
in supporting or sustaining human life or for a use which is of 
substantial importance in preventing impairment of human health, or 
(3) presents a potential unreasonable risk of illness or injury.

    Both class II and class III devices may present a potential 
unreasonable risk of illness or injury; however, the distinction is 
that devices in class II have sufficient evidence from which special 
controls can be established, in combination with general controls, that 
will provide a reasonable assurance of safety and effectiveness. As 
stated above, the CES proposed order indicated that there was 
insufficient evidence that would allow FDA to develop special controls 
that, in combination with general controls, would provide a reasonable 
assurance of safety and effectiveness of CES devices intended for 
treatment of depression, and FDA has determined that there is not 
sufficient new information that would satisfy that requirement to 
mitigate a potential unreasonable risk of illness or injury.
    (Response 2C) Some comments stated that CES for treatment of 
depression can be addressed by requiring clinical performance data to 
support a premarket notification (510(k)). However, in order to 
classify CES into class II for the treatment of depression, it is 
necessary for the evidence to first exist that permits the 
establishment of special controls to provide a reasonable assurance of 
safety and effectiveness. As mentioned above, FDA has conducted an 
extensive review of scientific literature and such evidence was not 
available at the time of the proposed order, and there continues to be 
a lack of effectiveness data to mitigate a potential unreasonable risk 
of illness or injury for CES devices for treatment of depression. 
Furthermore, there is lack of sufficient evidence to support 
development of special controls that would provide a reasonable 
assurance of safety and effectiveness for CES devices in treating 
depression.
    (Response 2D) A comment also stated that there is a prevalence of 
comorbidity of anxiety disorders and depression that supports the 
reclassification of CES for treatment of depression to class II. While 
the articles by Jansson-Frojmark et al. and Coplan et al. (Refs. 24 and 
25) discuss this connection, they are not studies of CES (as mentioned 
above) (Refs. 24 and 25). The available evidence where CES was 
investigated in an anxiety population where depression was a 
comorbidity is Barclay et al. (Ref. 6). This study, which investigated 
the use of CES to treat primary anxiety, also included subjects with 
``comorbid depression'' provided that a subject's anxiety was more 
severe than the depression (Ref. 6). However, the study does not 
clearly demonstrate that these subjects met the DSM 5 criteria for a 
recognized depressive disorder (Ref. 31). Therefore, the evidence is 
insufficient to enable FDA to establish a reasonable assurance of 
safety and effectiveness to support reclassifying CES devices intended 
for treatment of depression from class III to II.
    (Comment 3) A few comments supported the proposal for a call for 
PMAs for treatment of depression because they believed there was a lack 
of valid scientific evidence to support the effectiveness of CES 
devices for treatment of depression.
    (Response 3) FDA agrees with the comments to maintain the 
classification of CES for treatment of depression as class III. As 
stated in the preceding response, FDA has determined that there is a 
lack of sufficient evidence that would satisfy the requirement to 
mitigate ``a potential unreasonable risk of illness or injury'' to 
warrant the reclassification for depression into class II with special 
controls. As a result, there is insufficient evidence to establish 
special controls to provide a reasonable assurance of safety and 
effectiveness of CES devices for treatment of depression.
    (Comment 4) One comment compared the reclassification of CES with 
that of Electroconvulsive Therapy (ECT) devices. Specifically, the 
commenter states that FDA's reclassification of ECT devices, which 
provide the largest amount of electricity, to class II should equate to 
reclassification of CES devices, which provide less electricity, as 
class I.
    (Response 4) FDA disagrees with this commenter's comparison of ECT 
and CES devices. The safety and effectiveness evidence in support of 
reclassifying ECT for specific uses was substantial and demonstrated 
benefits more consistently, in comparison to the evidence evaluated for 
reclassifying CES intended for treatment of depression from class III 
to II, although sufficient information exists to establish special 
controls that, in addition to general controls, will provide reasonable 
assurance of safety and effectiveness of the CES devices intended for 
treatment of anxiety and/or insomnia, as discussed above. FDA assessed 
the totality of the valid scientific evidence that was provided in 
response to the proposed ECT order, including several comments that 
referenced new clinical studies. Several of these studies included 
safety and effectiveness data for adult as well as adolescent patients 
as well as randomized controlled clinical studies, open-label 
observational trials, case series reports, systematic literature 
reviews, and practice guidelines that were submitted in the comments. 
Additionally, the final order for the reclassification of ECT devices 
published in the Federal Register (December 26, 2018, 83 FR 66103) 
identifies ECT devices as applying a brief electrical stimulation of 
the brain to produce a seizure, while CES devices provide lower 
stimulation current that is not intended to result in seizure in 
patients. FDA also believes that general controls alone are 
insufficient to mitigate the risks to

[[Page 70009]]

health of CES devices; therefore, the special controls are also needed 
to provide reasonable assurance of safety and effectiveness for CES 
devices intended for treating anxiety and/or insomnia.
    (Comment 5) Several comments oppose the proposal to identify CES 
devices as prescription devices. Also, one comment opposes a 
prescription for treatment of depression and suggests that Federal and 
State laws mandate that physicians advise patients about CES before 
prescribing psychiatric, sleeping and/or pain medications so that 
patients can make a reasonable decision and possibly reduce medication-
induced mental health issues.
    (Response 5) As stated in the proposed order, the CES device is a 
prescription only device for all three intended uses, i.e., anxiety, 
insomnia, and depression, and may not be safe for use except under the 
authorization of a healthcare professional licensed by law to 
administer the use of the device. As such, the device identification in 
Sec.  882.5800(a) (21 CFR 882.5800(a)) has been revised to clarify that 
CES is a prescription device in accordance with 21 CFR 801.109. Per 
Sec.  801.109(c), a prescription device must include labeling that 
describes the indications and other information for use, such as 
methods, frequency and duration of administration, any relevant 
hazards, contraindications, side effects, and precautions under which 
the healthcare professionals can use the device safely (see Sec.  
882.5800(b)). Accordingly, healthcare professionals will have access to 
and be aware of the warnings and precautions in the labeling, and as 
such, healthcare professionals should be adequately informed of the 
risks associated with these devices. The healthcare professional can 
inform the patients of the relevant risks. The warning and precaution 
statements are an appropriate mitigation for CES intended for the 
treatment of anxiety and insomnia.
    (Comment 6) Several comments expressed the desire for insurance 
coverage to reduce the cost of the device.
    (Response 6) FDA understands the concerns with cost and insurance 
coverage. However, FDA has no authority over commercial health 
insurance carriers. Under sections 513(e) and 515(i) of the FD&C Act, 
FDA has no authority to consider as part of a classification decision 
whether an indication or a device is covered by commercial health 
insurance companies. FDA recommends that patients check with their 
insurance company regarding coverage before receiving CES treatment.
    (Comment 7) One comment stated that a manufacturer's website of a 
currently marketed CES device includes misleading marketing material 
that may persuade consumers to use this device. The comment also claims 
that the marketed CES device is not effective.
    (Response 7) FDA takes seriously any alleged claims of false or 
misleading claims by a device manufacturer. Several complaints have 
been received by the agency claiming that CES devices have not 
demonstrated effectiveness for treating anxiety and/or insomnia. FDA 
reviews all complaints and follows the appropriate steps to address 
complaints received. As a result, FDA continues to believe that the 
special controls proposed and finalized in this final order should 
include clinical performance data that demonstrates, among other 
things, that a CES device, when used as directed, will provide 
clinically meaningful results in the indicated patient population and 
provide a reasonable assurance of effectiveness for the intended use of 
CES devices for treating anxiety and/or insomnia. FDA also believes 
that a call for PMAs is appropriate for CES devices for treatment of 
depression to mitigate the potential unreasonable risk of illness or 
injury.
    (Comment 8) One comment suggested FDA should not rely on the 
recommendations of the 2012 Panel because the meeting was not conducted 
properly due to the following alleged errors by FDA: (1) Failure to 
include any panel members with the knowledge of or experience with CES 
devices; (2) failure to allow all interested parties ample time to 
present at the 2012 Panel; and (3) failure to provide adequate 
information by not presenting to the 2012 Panel for consideration the 
comments received from the proposed rule published in the Federal 
Register on August 8, 2011 (76 FR 48062), or articles of valid 
scientific evidence.
    (Response 8) FDA believes the 2012 Panel was properly conducted 
based on the requirements under the FD&C Act. FDA also disagrees with 
the alleged errors stated for the following reasons.
    First, FDA has specific procedures and protocols for all panel 
meetings that are followed to provide an objective outcome of the panel 
meetings. For more information, please refer to the FDA's Guidance, 
``Procedures for Meetings of the Medical Devices Advisory Committee'' 
(Ref. 32). Also, FDA may exclude a healthcare professional from 
participating on an advisory committee if the person has a conflict of 
interest. Although a healthcare professional was excluded from the 2012 
Panel, there was adequate representation of professionals with 
experience in using CES devices on the 2012 Panel. For more information 
on conflicts of interest as it relates to FDA advisory committees, 
please refer to the relevant FDA guidance entitled, ``Public 
Availability of Advisory Committee Members' Financial Interest 
Information and Waivers'' (Ref. 33).
    Second, under section 513(b)(6)(A)(iii) of the FD&C Act, any person 
whose device is specifically the subject of review by a panel shall 
have the same opportunity as the Secretary to participate in meetings 
of the panel, including, subject to the discretion of the panel 
chairperson, by designating a representative who will be provided a 
time during the panel meeting to address the panel for the purpose of 
correcting misstatements of fact or providing clarifying information, 
and permitting the person or representative to call on experts within 
the person's organization to address such specific issues in the time 
provided. Furthermore, section 513(b)(6)(B) of the FD&C Act, before and 
after the enactment of the 21st Century Cures Act (Pub. L. 114-255), 
requires that meetings shall provide adequate time for initial 
presentations; and encourage free and open participation by all 
interested persons. FDA provided the appropriate allocated time for all 
interested parties to speak or present at the 2012 Panel and for the 
2012 Panel to consider their concerns with CES devices (Ref. 32).
    Third, during the 2012 Panel, FDA's presentation included a listing 
of scientific articles (Refs. 1 and 2) and the 2011 proposed rule (76 
FR 48062) with a summary of the comments received to the docket for the 
proposed rule. Therefore, the 2012 Panel members received sufficient 
information on the 2011 proposed rule and other information to make an 
informed decision on the classification of CES devices.
    (Comment 9) Some comments questioned FDA's effectiveness claims for 
reclassification and suggested that more research is needed on CES 
before the device should be reclassified. One comment stated that the 
proposed order did not provide sufficient valid scientific evidence 
through tests to prove the effectiveness of CES for reclassification 
into class II because most of the studies conducted were inconclusive.
    (Response 9) FDA disagrees with these comments. The proposed order 
acknowledged that no individual published study on CES provides

[[Page 70010]]

definitive evidence of effectiveness of CES for the treatment of 
anxiety and/or insomnia. FDA noted, however, that in 18 of the 24 small 
published studies (those that enrolled fewer than 50 patients) that 
included assessments of anxiety and/or insomnia, each study had a main 
finding that indicated a greater benefit of CES versus control for at 
least 1 of the outcome measures evaluated. Furthermore, 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 (Refs. 5 and 6). 
Based on the available information, the proposed order concluded that 
there is valid scientific evidence of effectiveness for CES in the 
treatment of anxiety and/or insomnia. Since the proposed order was 
published, FDA has not become aware of new information that changes 
this position.
    Importantly, however, FDA acknowledges that 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 whether the devices, 
when used in accordance with such directions, will provide clinically 
meaningful results. As explained in the proposed order, although the 
evidence available to FDA collectively demonstrates a class effect of 
CES devices for treating anxiety and/or insomnia, it cannot be 
concluded, based on available information alone, that specific CES 
devices will be effective for treating anxiety and/or insomnia. As a 
result, FDA believes that the special controls must 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 and provide a reasonable assurance 
of safety and effectiveness for the intended use of CES devices for 
treating anxiety and/or insomnia.
    (Comment 10) One comment recommended that FDA should obtain valid 
scientific evidence which supports that Central Nervous System (CNS) 
disorders are treatable with the use of CES.
    (Response 10) The category of ``CNS disorders'' is very broad, 
while the classification of CES devices is only based on the treatment 
of anxiety, insomnia and/or depression, as they are the only 
indications that have been currently allowed for marketing 
authorization; therefore, valid scientific evidence for all CNS 
disorders are not relevant for this reclassification. This final order 
does not address the treatment of broader CNS disorders as they are 
outside the scope of this final order. Manufacturers seeking to 
indicate a device for a specific CNS disorder would be responsible for 
the collection of any valid scientific evidence that may be necessary 
to support a new indication for marketing CES devices.
    (Comment 11) One comment suggests that FDA should correctly 
categorize CES as either Direct Current (DC) or Alternating Current 
(AC) stimulation and not whether it is the same waveform as the 
predicate CES devices used. Comment also suggests that clinical trials 
are necessary to determine regions of influence by current.
    (Response 11) Based on our interpretation of this comment, FDA 
believes that CES devices could use AC or DC stimulation and that 
clinical trials conducted to comply with the special controls could be 
used to characterize the degree of activation in different brain 
regions.

IV. The Final Order

    Based on the information discussed in the preamble to the proposed 
order (81 FR 3751), the comments received for the proposed order, a 
review of medical device reports in the FDA MAUDE database, a review of 
current scientific literature, and 2012 Panel deliberations (Ref. 1), 
FDA concludes that special controls, in conjunction with general 
controls, will provide reasonable assurance of the safety and 
effectiveness of CES devices intended for treatment of anxiety and/or 
insomnia. Under sections 513(e), 515(b), and 515(i) of the FD&C Act, 
FDA is adopting its findings, as published in the preamble to the 
proposed order. For the reasons described in section III, FDA is 
issuing this final order to reclassify CES devices intended for 
treatment of anxiety and/or insomnia from class III to class II 
(special controls). CES devices intended to treat anxiety and/or 
insomnia 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 anxiety and/or insomnia until 1 year after 
the effective date of the final order.
    Section 510(m) of the FD&C Act provides that FDA may exempt a class 
II device from the premarket notification requirements under section 
510(k) of the FD&C Act, if FDA determines that premarket notification 
is not necessary to provide reasonable assurance of the safety and 
effectiveness of the device. For the CES devices classified as class II 
(i.e., for treatment of anxiety and/or insomnia), FDA has determined 
that premarket notification is necessary to provide reasonable 
assurance of the safety and effectiveness of the device. Therefore, 
this device type is not exempt from premarket notification 
requirements. Persons who intend to market this type of device must 
submit to FDA a premarket notification, prior to marketing the device, 
which contains information about the device they intend to market.
    FDA is also requiring the filing of a PMA for CES devices intended 
for the treatment of depression under section 515(b) of the FD&C Act. 
Under section 515(b)(1)(A) of the FD&C Act, PMAs for CES devices are 
required to be filed on or before 90 days after the effective date of a 
final order.

V. Implementation Strategy

A. Date To File a PMA

    In accordance with section 515(b) of the FD&C Act, CES devices 
intended to treat depression must have a PMA or a notice of completion 
of PDP filed with the Agency by March 19, 2020. An applicant whose 
device was legally in commercial distribution before May 28, 1976, or 
whose device has been found to be substantially equivalent to such a 
device, will be permitted to continue marketing such class III devices 
during FDA's review of the PMA provided that the PMA is timely filed. 
For currently legally marketed CES devices intended to treat 
depression, FDA does not intend to enforce compliance with this 90-day 
requirement for an additional 90 days (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

[[Page 70011]]

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.'' If a 
PMA for a class III device is not filed with FDA by March 19, 2020, the 
device will be deemed adulterated under section 501(f) of the FD&C Act. 
Table 2 shows the 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   Distribution period
                                   to enforce            (time after
                                compliance (time      effective date of
                              after effective date      final order)
                                 of final order)
------------------------------------------------------------------------
Intent to file a PMA........  90 days.............  Devices included in
                                                     an intent to file:
                                                     180 days.
File a PMA..................  Devices included in   Until a not
                               an intent to file:    approvable decision
                               180 days.             or denial decision
                              Devices not included   is issued; can
                               in an intent to       continue
                               file: 90 days.        distribution if an
                                                     approval order is
                                                     issued.
------------------------------------------------------------------------

    Under Sec.  812.2(d), the exemption 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 CES devices indicated for 
depression that are: (1) Not legally on the market on or before March 
19, 2020 or (2) legally on the market on or before March 19, 2020 but 
for which a PMA or notice of completion of a PDP is not filed by March 
19, 2020, or for which PMA approval has been denied or withdrawn.
    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 March 
19, 2020 to avoid interrupting investigations. 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. Compliance With Special Controls

    Following the effective date of this final order, CES devices 
intended to treat anxiety and/or insomnia must comply with the special 
controls. 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 to treat insomnia and/or 
anxiety, may remove such intended uses from the device's labeling.
    The special controls identified in this final order are effective 
as of the date of publication of this order, December 20, 2019. CES 
devices intended to treat anxiety and/or insomnia must comply with the 
special controls following the effective date of this order. However, 
FDA does not intend to enforce compliance with the special controls for 
currently legally marketed CES devices intended to treat anxiety and/or 
insomnia until 1 year after the effective date of the final order. 
Manufacturers who wish to continue to legally market a CES device for 
treatment of anxiety and/or insomnia must submit an amendment to their 
previously cleared 510(k) that demonstrates compliance with the special 
controls by December 21, 2020. 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 is not submitted by 
December 21, 2020 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 anxiety and/or insomnia 
that have not been legally marketed prior to December 20, 2019, or 
models that have been legally marketed but are required to submit 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.

VI. Codification of Orders

    Sections 513(e) and 515(b), as amended by FDASIA, and 515(i) of the 
FD&C Act require FDA to issue final orders rather than regulations to 
reclassify devices. Therefore, FDA will continue to codify 
reclassifications and requirements for approval of an application for 
premarket approval, resulting from changes issued in final orders, in 
the Code of Federal Regulations. Accordingly, under sections 
513(e)(1)(A)(i) and 515(b) of the FD&C Act, as amended by FDASIA and 
FDA's Medical Device Classification Procedures final rule (83 FR 
64443), in this final order, we are codifying the amendment of 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 anxiety 
and/or insomnia as class III devices and codifying the reclassification 
of CES devices intended to treat anxiety and/or insomnia to class II 
(special controls); (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 the requirement of approval 
of an application for premarket approval, as described in section IV; 
and (3) clarifying the device identification of CES devices to include 
it as a prescription device.

VII. Analysis of 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.

VIII. Paperwork Reduction Act of 1995

    This final order refers to previously approved collections of 
information that are subject to review by the Office of Management and 
Budget (OMB) under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 
3501-3521). The collections of information in part 807,

[[Page 70012]]

subpart E, have been approved under OMB control number 0910-0120. The 
collections of information in part 812 have been approved under OMB 
control number 0910-0078. The collections of information in 21 CFR part 
814, subparts A through E have been approved under OMB control number 
0910-0231. The collections of information in part 801 have been 
approved under OMB control number 0910-0485. The collections of 
information in 21 CFR part 820 have been approved under OMB control 
number 0910-0073.

IX. References

    The following references marked with an asterisk (*) are on display 
at the Dockets Management Staff (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, and 
are available for viewing by interested persons between 9 a.m. and 4 
p.m., Monday through Friday; they also are available electronically at 
https://www.regulations.gov. References without asterisks are not on 
public display at https://www.regulations.gov because they have 
copyright restriction. Some may be available at the website address, if 
listed. References without asterisks are available for viewing only at 
the Dockets Management Staff. FDA has verified the website addresses, 
as of the date this document publishes in the Federal Register, but 
websites are subject to change over time.

*1. Transcript, February 10, 2012, meeting of the Neurological 
Devices Panel of the Medical Device Advisory committee, available at 
https://wayback.archive-it.org/7993/20170403223434/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM296891.pdf.
*2. FDA Executive Summary, Prepared for the February 10, 2012, 
meeting of the Neurological Device Panel at https://wayback.archive-it.org/7993/20170404140724/https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/NeurologicalDevicesPanel/UCM290787.pdf.
*3. FDA, Reclassification of Daily Wear Spherical Contact Lenses 
Consisting of Rigid Gas Permeable Plastic Materials; Withdrawal of 
Proposed Rule. 48 FR 56778 to 56798, 1983.
*4. FDA Guidance, ``Use of Real-World Evidence to Support Regulatory 
Decision-Making for Medical Devices,'' August 2017, available at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-real-world-evidence-support-regulatory-decision-making-medical-devices.
*5. Lande, R.G. and C. Gragnani, ``Efficacy of Cranial Electric 
Stimulation for the Treatment of Insomnia: A Randomized Pilot 
Study.'' Complementary Therapies in Medicine 21:8-13, 2012.
*6. Barclay, T.H. and R.D. Barclay, ``A Clinical Trial of Cranial 
Electrotherapy Stimulation for Anxiety and Comorbid Depression.'' 
Journal of Affective Disorders 164:171-177, 2014.
*7. Rosenthal, S.H., ``Electrosleep: A Double-Blind cClinical 
Study.'' Biological Psychiatry 4(2):179-185, 1972.
*8. Levitt, E.A., N. James, and 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.
*9. Passini, F.G., C.G. Watson, and 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.
*10. Scallet, A., R. Cloninger, and 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.
*11. Feighner, J.P., S.L. Brown, and J.E. Olivier, ``Electrosleep 
Therapy: A Controlled Double Blind Study.'' Journal of Nervous and 
Mental Disease 157(2):121-128, 1973.
*12. Hearst, E.D., C.R. Cloninger, E.L. Crews, and R.J. Cadoret, 
``Electrosleep Therapy: A Double-Blind Trial.'' Archives of General 
Psychiatry 30(4):463-466, 1974.
*13. Flemenbaum, A., ``Cerebral Electrotherapy (electrosleep): An 
Open Clinical Study With a Six Month Follow Up.'' Psychosomatics 
15(1):20-24, 1974.
*14. Rosenthal, S.H. and N.L. Wulfsohn, ``Electrosleep: A 
Preliminary Communication.'' Journal of Nervous and Mental Disease 
151(2):146-151, 1970.
*15. Matteson, M.T. and 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.
*16. 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.
*17. Moore, J.A., C.S. Mellor, K.F. Standage, and H. Strong, ``A 
Double Blind Study of Electrosleep for Anxiety and Insomnia.'' 
Biological Psychiatry 10(1):59-63, 1975.
*18. Marshall, A.G. and C.E. Izard, ``Cerebral Electrotherapeutic 
Treatment of Depressions.'' Journal of Consulting and Clinical 
Psychology 42(1):93-97, 1974.
*19. Kirsch, D., Ph.D., et al., ``Military Service Member and 
Veteran Self Reports of Efficay of Cranial Electrotheraphy 
Stimulation for Anxiety, Posttraumatic Stress Disorder, Insomnia, 
and Depression.'' The United States Army Medical Journal, Oct.-Dec. 
2014.
*20. Mellen, R.R. and W. Mackey, ``Reducing Sheriff's Officers' 
Symptoms of Depression Using Cranial Electrotherapy Stimulation 
(CES): A Control Experimental Study.'' The Correctional 
Psychologist, 41(1):9-15, 2009.
*21. Lu, X.Y., A.H.Wang, Y. Li, J.S. Zhang, and B.X. Liu, ``Safety 
and Effectiveness of Cranial Electrotherapy Stimulation in Treating 
Children with Emotional Disorders.'' Chinese Journal of Clinical 
Rehabilitation, 9(8):96-7, 2005.
*22. McClure, D. et al., ``A Pilot Study of Safety and Efficacy of 
Cranial Electrotherapy Stimulation in Treatment of Bipolar II 
Depression.'' The Journal of Nervous and Mental Disease, vol. 
203(11):827-35, 2011.
*23. Chen, Y., Y. Lin, Z. Jiuping, L. Lejia, et al., ``Results of 
Cranial Electrotherapy Stimulation to Children with Mixed Anxiety 
and Depressive Disorder.'' Shanghai Archives of Psychiatry, 
19(4):203-205, 2007.
*24. Jansson-Fr[ouml]jmark M., and K. Lindblom, ``A Bidirectional 
Relationship Between Anxiety and Depression, and Insomnia? A 
Prospective Study in the General Population.'' Journal Psychosomatic 
Research, 64(4):443-9, April 2008.
*25. Coplan J.D., C.J. Aaronson, V. Panthangi, and Y. Kim, 
``Treating Comorbid Anxiety and Depression: Psychosocial and 
Pharmacological Approaches.'' World Journal of Psychiatry, 5(4):366-
78, Dec. 2015.
*26. Bystritsky, A., L. Kerwin, and J. Feusner, ``A Pilot Study of 
Cranial Electrotherapy Stimulation for Generalized Anxiety 
Disorder.'' Journal of Clinical Psychiatry, 69(3):412-417, March 
2008.
*27. Yennurajalingam, S., D.H. Kang, W.J. Hwu, N.S. Padhye, et al., 
``Cranial Electrotherapy Stimulation for the Management of 
Depression, Anxiety, Sleep Disturbance, and Pain in Patients With 
Advanced Cancer: A Preliminary Study.'' Journal of Pain and Symptom 
Management, 55(2):198-206, Feb. 2018.
    *28. Bhardwaj, M., N. Arumugam, and S. Gambhir, ``Efficacy of 
Cranial Electrical Stimulation and Rational Emotive Behavior Therapy 
in Improving Psychological Illness among Chronic Stroke Survivors: A 
Pilot Randomized Controlled Trial.'' Annals of Indian Academy of 
Neurology, 21(3):188-192, Jul.-Sept. 2018.
    *29. Gong, B.Y., H.M. Ma, X.Y. Zang, S.Y. Wang, et al., 
``Efficacy of Cranial Electrotherapy Stimulation Combined with 
Biofeedback Therapy in Patients with Functional Constipation.'' 
Journal of Neurogastroenterol Motility, 22(3):497-508, July 2016.
    30. Lande, R.G. and C.T. Gragnani, ``Prospective Study of Brain 
Wave Changes Associated With Cranial Electrotherapy Stimulation.'' 
The Primary Care Companion for CNS Disorders, 18;20(1), Jan. 2018, 
available at https://www.psychiatrist.com/PCC/article/Pages/2018/v20n01/17m02214.aspx.
    31. American Psychiatric Association, Diagnostic and Statistical 
Manual of Mental Disorders (5th ed.). Arlington, VA, 2013.
    *32. FDA Guidance, ``Procedures for Meetings of the Medical 
Devices Advisory Committee,'' September 2017, available at

[[Page 70013]]

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/procedures-meetings-medical-devices-advisory-committee.
    *33. FDA Guidance, ``Public Availability of Advisory Committee 
Members' Financial Interest Information and Waivers,'' March 2014, 
available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/public-availability-advisory-committee-members-financial-interest-information-and-waivers.

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, 21 CFR part 
882 is amended as follows:

PART 882--NEUROLOGICAL DEVICES

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

    Authority:  21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 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 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; and
    (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 March 19, 2020, for any cranial 
electrotherapy stimulator device with an intended use described in 
paragraph (b)(2) of this section, that was in commercial distribution 
before May 28, 1976, or that has, on or before March 19, 2020, been 
found to be substantially equivalent to any cranial electrotherapy 
stimulator device with an intended use described in paragraph (b)(2) 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)(2) of this section shall have an approved 
PMA or declared completed PDP in effect before being placed in 
commercial distribution.

    Dated: December 13, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-27295 Filed 12-19-19; 8:45 am]
BILLING CODE 4164-01-P