[Federal Register Volume 83, Number 246 (Wednesday, December 26, 2018)]
[Rules and Regulations]
[Pages 66103-66124]
[FR Doc No: 2018-27809]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 882

[Docket No. FDA-2014-N-1210]

Neurological Devices; Reclassification of Electroconvulsive
Therapy Devices; Effective Date of Requirement for Premarket Approval
for Electroconvulsive Therapy Devices for Certain Specified Intended
Uses

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final
order to reclassify the electroconvulsive therapy (ECT) device for use
in treating catatonia or a severe major depressive episode (MDE)
associated with major depressive disorder (MDD) or bipolar disorder
(BPD) in patients age 13 years and older who are treatment-resistant or
who require a rapid response due to the severity of their psychiatric
or medical condition, which is a preamendments class III device, into
class II (special controls). 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 the
preamendments class III ECT devices for all other uses that are not
being reclassified to class II (product code GXC).

DATES: This order is effective on December 26, 2018. See further
discussion in section V, Implementation Strategy.

FOR FURTHER INFORMATION CONTACT: Carlos Pe[ntilde]a, Center for Devices
and Radiological Health, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 66, Rm. 2680, Silver Spring, MD 20993, 301-796-
6610<EMAIL_ADDRESS>
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 Responding to the Proposed Order
    A. Comments in Support of Reclassifying ECT Into Class II
    B. Comments on Reclassifying ECT Based on Safety and
Effectiveness
    C. Comments on Patient Concerns
    D. Comments on Regulatory Process of the Proposed Order
    E. Comments on Labeling Concerns
    F. Comments Outside the Scope of This Final 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

                   Table of Abbreviations and Acronyms
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      Abbreviation  or acronym                  What it means
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510(k).............................  Premarket Notification.
2011 Panel.........................  2011 Neurological Devices Panel
                                      Meeting.
AACAP..............................  American Academy of Child and
                                      Adolescent Psychiatry.
APA................................  American Psychiatric Association.
BPD................................  Bipolar Disorder.
CANTAB.............................  Cambridge Neuropsychological Test
                                      Automated Battery.
CFR................................  Code of Federal Regulations.
CGI-I..............................  Clinical Global Impressions-
                                      Improvement scale.
ECT................................  Electroconvulsive Therapy Device.
FDA................................  Food and Drug Administration.
FDARA..............................  FDA Reauthorization Act of 2017.
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.
MDD................................  Major Depressive Disorder.
MDE................................  Major Depressive Episode.
MDR................................  Medical Device Reporting.
M-ECT..............................  Maintenance ECT.
MMSE...............................  Mini Mental State Exam.
OMB................................  Office of Management and Budget.
PDP................................  Product Development Protocol.
PMA................................  Premarket Approval Application.
PRA................................  Paperwork Reduction Act of 1995.
Ref................................  Reference
RWD................................  Real-World Data.
RWE................................  Real-World Evidence.
SE.................................  Safety and Effectiveness.
U.S.C..............................  United States Code.
WFSBP..............................  World Federation of Societies of
                                      Biological Psychiatry.
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II. Background

    The Federal Food, Drug, and Cosmetic Act (FD&C Act), 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 (SE). 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) \1\ 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).
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    \1\ ECT devices with intended uses outside the scope of those
listed in paragraphs 21 CFR 882.5940(b)(1) and (2) are considered
postamendments device, 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.
    On August 18, 2017, section 513(f) of the FD&C Act was amended by
the FDA Reauthorization Act of 2017 (FDARA; Pub. L. 115-52). Under
section 513(f)(6) of the FD&C Act, FDA has authority to issue an
administrative order classifying an accessory based on the risks of the
accessory when used as intended and the level of regulatory controls
necessary to provide a reasonable assurance of SE of the accessory,
notwithstanding the classification of any other device with which such
accessory is intended to be used. FDA's ``Medical Device Accessories--
Describing Accessories and Classification Pathways'' guidance describes
the statutory mechanisms to request: (1) Classification for accessories
that have been granted marketing authorization as part of a PMA,
premarket notification (510(k)), or De Novo request for another device
with which the accessory involved is intended to be used and (2)
classification for accessories included in a PMA or 510(k) that FDA has
not classified distinctly from another device under the FD&C Act (Ref.
1).

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 SE, but for which there is
sufficient information to establish special controls to provide a
reasonable assurance of SE of a device.
    FDA published a proposed order in the Federal Register of December
29, 2015 (80 FR 81223), held a meeting of a device classification panel
on January 27-28, 2011, as described in section 513(b) of the FD&C Act
with respect to ECT devices, and considered comments from public
dockets, and, therefore, has met the requirements under sections
515(i)(2) of the FD&C Act.

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. As noted above, FDA has published a proposed order that
would require PMAs for an electroconvulsive therapy device for certain
uses other than a severe MDE associated with MDD or BPD, in the Federal
Register of December 29, 2015. FDA has held a meeting of a device
classification panel described in section 513(b) of the FD&C Act with
respect to ECT devices. Finally, FDA has received and has considered
over 3,400 comments on the proposed order, as discussed in section II.
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 section 515(b) of the FD&C Act, changing the
mechanism for requiring premarket approval for a preamendments device
from rulemaking to an administrative order.
    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) 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. Because ECT devices were classified in 1979, the
30-month period has expired (44 FR 51776, September 4, 1979), and the
later of these two time periods is the 90-day period. Therefore, if a
PMA is not filed for ECT devices for certain specified intended uses
within 90 days after the issuance of a final order, the device will be
deemed adulterated under section 501(f) of the FD&C Act.
    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 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. 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 SE 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 that was provided in response to the proposed
order, including several comments that referenced additional clinical
studies. Several of these studies included SE data for adult as well as
adolescent patients. FDA also considered randomized controlled clinical
studies, open-label observational trials, case series reports,
systematic literature reviews, and practice guidelines 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.
    FDA received many comments from healthcare professionals describing
their practices, the length of time they have been practicing, and the
utilization of ECT devices in treating patients with certain
conditions. While FDA acknowledges receiving comments in support of the
proposed reclassification, statements by individual healthcare
professionals that they have used ECT devices to treat individual
patients do not constitute valid scientific evidence to demonstrate
reasonable assurance of SE (see valid scientific evidence discussion in
48 FR 56778 at 56786-56788, comments 16-21, December 23, 1983, Ref. 2).
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 judgement.
    FDA also received many comments from patients, or friends and
family of patients, in support and against reclassification of ECT
devices. These comments described the experience of the patient that
received treatment from an ECT device. FDA acknowledges receiving
comments from patients and other individuals about their experience
with the device being considered for reclassification; however, FDA
does not consider such comments to be valid scientific evidence.
Because these comments did 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 judgement, such comments are not considered valid scientific
evidence.
    For medical devices, available evidence is traditionally comprised
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
guidance, ``Use of Real-World Evidence to Support Regulatory Decision-
Making for Medical Devices'' (82 FR 41418, August 31, 2017, Ref. 3),
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 identifying a device, the SE of which is questionable, Sec.
860.7(c)(2) also explains random experience and reports lacking
sufficient details to permit scientific evaluation may be considered
valid scientific evidence. Such random experience and reports lacking
sufficient details to permit scientific evaluation may be early and
sometimes informal indications of the danger or ineffectiveness of a
device (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.

III. Public Comments in Response to the Proposed Order

    On December 29, 2015, FDA published a proposed order to reclassify
from class III to class II the ECT device for use in treating a severe
MDE associated with MDD or BPD in patients 18 years of age and older
who are treatment-resistant or who require a rapid response due to the
severity of their psychiatric or medical condition and to require the
filing of a PMA for ECT devices for the intended uses of schizophrenia,
bipolar manic states, schizoaffective disorder, schizophreniform
disorder, and catatonia. The comment period on the proposed order
closed on March 28, 2016.
    In response to the December 29, 2015, proposed order, FDA received
over 3,400 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 over 3,400 comments are grouped based on the common themes listed
below. We have grouped similar comments together under the same number
and numbered them sequentially.

A. Comments in Support of Reclassifying ECT Into Class II (Comments 1-
2)
B. Comments on Reclassifying ECT Based on Safety and Effectiveness
(Comments 3-9)
C. Comments on Patient Concerns (Comments 10-16)
D. Comments on Regulatory Process of the Proposed Order (Comments 17-
23)
E. Comments on Labeling Concerns (Comments 24-29)
F. Comments Outside the Scope of This Final Order (Comments 30-34)

    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. 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.
    In the proposed order we asked interested persons to submit
comments on two specific questions. FDA sought comments on whether: (1)
The term ``treatment resistant'' and the phrase ``require rapid
response'' provide sufficient clarity to the population for which ECT
benefits outweigh risks and (2) if 60 days is an appropriate time to
allow existing manufacturers who do not intend to market their ECT
device(s) for uses other than use in treating severe MDE associated
with MDD and BPD in patients 18 years of age and older who are
treatment-resistant or who require a rapid response due to the severity
of their psychiatric or medical condition to prepare and submit 510(k)
amendments for ECT devices. FDA continues to believe the term
``treatment resistant'' and the phrase ``require rapid response''
provide sufficient clarity to the population for which ECT benefits
outweigh risks. Because there were no comments submitted on the second
question, FDA's discussion of when 510(k) holders should submit an
amendment to a 510(k) is in section V.B., Compliance with Special
Controls, of this final order.

A. Comments in Support of Reclassifying ECT Into Class II

    (Comment 1) FDA received many comments generally supporting the
proposed reclassification to class II. Comments included many
literature references including references published since the 2011
Neurological Devices Classification Panel meeting (the 2011 Panel).
Several comments noted that ECT had been used safely and effectively in
their practice or on themselves as a patient or on a family member or a
friend.
    (Response 1) After examination of the totality of the scientific
evidence, FDA continues to believe that there is sufficient evidence to
establish special controls that, together with general controls,
provide a reasonable assurance of SE to reclassify ECT to class II for
use in treating a severe MDE associated with MDD or BPD, as initially
specified in the proposed order. In addition, FDA has determined that
there is adequate support for the reclassification of ECT into class II
for the treatment of catatonia and expanding the adolescent age
subpopulation from 18 to 13 years of age. FDA has made this
determination based upon a reassessment of the following sources of
information: (1) Published literature referenced in the Executive
Summary to the 2011 Panel; (2) comments and literature received in
public dockets including the call for SE information for all
preamendments class III devices (74 FR 16214, April 9, 2009), the call
for ECT SE information in a separate docket (74 FR 46607, September 10,
2009), the 2011 Panel (75 FR 72832, November 26, 2010), the ECT Draft
Guidance (80 FR 81330, December 29, 2015) and the proposed order
(December 29, 2015) (these five dockets are to be referred to as ``ECT
public dockets'' in this document, discussed below in response 2); (3)
clinical practice guidelines; and (4) 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 2011 Panel meeting, and the review of
additional post-2011 scientific information that was provided to FDA in
comments to the proposed order, further supports this finding.
    (Comment 2) Several comments supported the reclassification of ECT
to class II for a severe MDE associated with MDD or BPD, but said the
reclassification was too restrictive in its scope. Several additional
indications, many of which are outside the scope of this classification
effort, were mentioned. Comments suggested that classification should
be expanded to some or all of the following indications and populations
(ordered alphabetically):

 Adolescents
 Adolescents and children
 Autism
 Catatonia
 Delirium
 Delusional disorders
 Developmental disability
 Maintenance or continuation ECT
 Mania in BPD
 Mania--refractory, intractable, acute
 Neuroleptic malignant syndrome
 Other psychiatric disorders and conditions for which ECT has
been used
 Parkinson's disease
 Patients with contraindications to drug treatment including
women who are pregnant/nursing, the elderly, or those who have comorbid
conditions
 Psychosis--treatment resistant, puerperal
 Schizophrenia--clozapine resistant, refractory
 Schizoaffective disorder
 Severe self-injurious behavior
 Shy-Drager syndrome
 Status epilepticus
 Suicidal patients

    (Response 2) As part of the review of the public comments received
in response to the proposed order, FDA considered over 400 scientific
articles cited in comments or attached to comments filed in the ECT
public dockets. Many of the scientific articles included information
not within the scope of this order; however, some of the articles
included studies that investigated the SE of ECT for catatonia, mania,
schizophrenia, and schizoaffective disorder, and use of ECT in
children, adolescents, and adults, which are indications within the
scope of this final order. Many of these articles also provided
information on research published since 2010, after the literature
review was conducted for the 2011 Panel on classification of ECT
devices.
    Of the information submitted in response to the proposed order, FDA
reviewed many articles containing valid scientific evidence regarding
the SE of ECT for certain intended uses, which are within the scope of
this reclassification effect, including catatonia and severe MDE
associated with MDD or BDP for the indicated populations. In addition,
29 articles referenced in the ECT public dockets contain valid
scientific evidence on the SE of ECT in the adolescent subpopulation
(patients age 13 years to less than 18 years). The sections below
further discuss FDA's review of this evidence and conclusions.
    Based on evaluation of this evidence, FDA is including in the final
order to reclassify ECT the indication of catatonia for patients who
are treatment-resistant or who require a rapid response due to the
severity of their psychiatric or medical condition in addition to
treating a severe MDE (associated with MDD or BPD). FDA believes that
the totality of evidence supports the determination that the special
controls identified in this final order, along with general controls,
are sufficient to provide a reasonable assurance of SE for these
indications. For the other indications cited in the ECT public dockets
that are within the scope of this classification effort, FDA has
concluded that there was insufficient scientific evidence to support
reclassification.
    Several comments posted to the ECT public docket in response to the
proposed order, including comments from professional societies and
organizations, physicians, and other ECT practitioners, were supportive
of a class II recommendation for catatonia or a severe MDE associated
with MDD or BPD in adolescents, and in some cases, younger children.
While ECT devices are historically cleared with no specific age
indicated, the proposed order for ECT recommended that the indications
for use be limited to use of the device in patients 18 and above.
Consistent with the cleared indications, FDA's Executive Summary for
the 2011 Panel to discuss reclassification did not include a review on
the use of ECT in different age groups; however, substantive comments
were provided during the open public hearing section both for and
against the use of ECT in children and adolescents (Ref. 4). In
response to the comments recommending expansion of the age range of
adolescent patients, under section 515(i)(2) of the FD&C Act, FDA
assessed the articles submitted in the ECT public dockets (sources of
information listed in response to Comment 1 above) to evaluate the SE
evidence supporting the use of ECT in younger populations (i.e.,
children and adolescents).
    FDA evaluated ECT use in treating a number of psychiatric or
medical conditions (e.g., a severe MDE associated with MDD or BPD,
catatonia, schizophrenia, schizoaffective disorder, and mania) in these
younger populations. Limited experience and only a few reports were
available for patients less than and including 12 years of age (i.e.,
children). The majority of studies focused on catatonia or a severe MDE
associated with MDD or BPD in patients age 13 years and older.

For those studies that did report clinical outcomes in adolescent
patients, results were generally favorable in treating catatonia or a
severe MDE associated with MDD or BPD. Treatment approaches (i.e.,
electrode placement, administration, and safeguards) were similar
between adult and adolescent subpopulations. As such, the literature
provided in the ECT public dockets supports a reclassification to class
II for the use of ECT in treating catatonia or a severe MDE associated
with MDD or BPD, for patients age 13 years and older who are treatment-
resistant and who require a rapid response due to the severity of their
psychiatric or medical condition, with the establishment of special
controls (discussed in more detail below in section III.A.3). FDA's
evaluation is based on a reassessment of the published literature
referenced in the Executive Summary to the 2011 Panel, comments and
literature received in the ECT public dockets, and review of the 2011
Panel meeting transcript.
    Based upon FDA's review of the scientific literature submitted in
the comments received in the ECT public dockets, and an assessment of
the totality of the evidence, FDA is reclassifying ECT devices for a
broader population than identified in the proposed order. The
reassessment of evidence including scientific articles are organized
into four subsections consisting of: (1) Safety of ECT in treating
catatonia or a severe MDE associated with MDD or BPD; (2) effectiveness
of ECT for catatonia; (3) effectiveness of ECT for patients 13 years
and older; and (4) effectiveness of ECT for schizophrenia,
schizoaffective disorder, and mania. The specific indications within
the scope of this final order include only those for which FDA has
cleared 510(k) submissions. In this summary, we do not include isolated
case reports.
1. Safety of ECT in Treating Catatonia or a Severe MDE Associated With
MDD or BPD
    Overall, the published literature provided since 2010 in the
comments received in the ECT public dockets and reviewed by FDA
provided information on over 1,000 patients, and included information
regarding ECT treatment outcomes in adults, adolescents, and children.
The reviewed published literature included prospective and
retrospective studies, randomized patient treatment schedules (e.g.,
number of treatments per week), and either administered unilateral or
bilateral stimulation. The majority of studies reported the safe use of
ECT with minimal and reversible adverse events, and in some cases,
patient memory and mood improved while treating catatonia or a severe
MDE associated with MDD or BPD; positive results included outcomes in
both adults and adolescent subpopulations. Six studies (Refs. 5-10)
provided detailed safety data on patients (N=609) for review and
further discussion below.
    Fernie et al. (Ref. 5) conducted a retrospective study to evaluate
the persistence of cognitive side effects of ECT in a retrospective
case study of 126 patients treated with ECT between June 2010 and
October 2012 at the Royal Cornhill Hospital, Aberdeen, Scotland.
Results from validated longitudinal neuropsychological tests (the
Cambridge Neuropsychological Test Automated Battery spatial recognition
memory test (CANTAB)) and subjective reports of memory function showed
that while the performance was poorer compared with baseline for tests
administered up to 3 months following completion of ECT therapy, these
effects were transient and improved at 6 months. In some cases, mood
and subjective memory scores improved following ECT. The Mini Mental
State Exam (MMSE) demonstrated improvement over baseline starting from
1 month following therapy. Overall, the application of ECT had
reversible cognitive deficiencies compared to pre-ECT treatment scores,
a measure of safety, and in some assessments (CANTAB, subjective
reports of memory function, and MMSE) showed patient improvement.
    Kirov et al. (Ref. 6) conducted a retrospective review of 10 years
of cognitive performance data that included 199 patients and 500
assessments. Cognitive testing consisted of a battery of nine tests
including backward digit span, word, shape, and face recognition,
verbal fluency, complex figure immediate recall, and trail making. Not
all subjects were capable of performing all tests and parts of the
battery changed over time. Results (linear mixed regression analyses)
demonstrated that age, severity of depression at the time of testing,
and number of days since the last ECT session were the major factors
affecting cognitive performance, but the total number of previous ECT
sessions did not have a measurable impact on cognitive performance,
which further supports the safety of ECT in not leading to cumulative
cognitive deficits.
    Maric et al. (Ref. 7) prospectively studied 30 patients with MDD at
baseline, shortly after ECT treatment, and at 1 month post treatment
using the learning and visual, spatial, and figural memory tests of
CANTAB. Severity of depressive symptoms as measured by healthcare
professional-rated and self-rated instruments was significantly reduced
over time with treatment, as a measure of the effectiveness of ECT. At
the same time, the neuropsychological tests did not detect any
significant memory impairment and showed improvement on visual memory
and learning at 1 month and in the immediate post-treatment period,
indicating no prolonged or significant ECT-related memory deficits.
These improvements correlated with improvement in depression while
serious adverse events were not reported.
    Spaans et al. (Ref. 8) compared unilateral brief pulse ECT with
unilateral ultra-brief pulse ECT for the treatment of major depression.
In this double-blind randomized study conducted in 3 tertiary
psychiatric hospitals in the Netherlands, 116 patients entered the
study and of those, 87 completed the study (until remission or 12
treatments). Seventy-six (n=76) patients were available with pre- and
post-ECT assessments. Blinded cognitive assessment was done before ECT
treatment was started and again within 2 days to a week after all
treatments were completed. Patients on average received about eight
treatments (average 7.1 in the brief pulse group vs. 9.2 in the ultra-
brief pulse group). To assess cognitive function, several
neuropsychological tests were administered including the
Autobiographical Memory Interview and the Amsterdam Media
Questionnaire, which is a public event questionnaire with questions
grouped by decade about events from the decades of the 1970s through
the 2000s. Other cognitive domain tests were also conducted. No
significant difference was seen in retrograde amnesia between the two
treatment groups. Change in recall performance and fluency tests were
also similar between the two groups. There was not a significant
difference in performance in the cognitive tests following ECT for any
of the cognitive tests during the course of study. The authors also
reported mitigating adverse effects on cognition by lengthening the
time between treatments to provide patients with more time to
recuperate, thereby further characterizing how ECT treatment can be
applied safely.
    Semkovska et al. (Ref. 9) prospectively studied 138 patients with
major depressive episodes who were treated in a national ECT study in
which patients were randomly assigned to receive bitemporal (69
patients) or right-side unilateral ECT (69 patients). This

study included 3-month and 6-month followup assessments. Adverse events
were similar for the unilateral and bitemporal groups. Following
treatment, headache was the most commonly reported adverse physical
effect (approximately 27 percent of subjects). Nausea (approximately 14
percent), and muscle pain (approximately 10 percent) were also
reported. Significant acute adverse events associated with treatment
included six patients (4 unilateral, 2 bitemporal) who experienced ECT
related hypertension. Also, one patient developed laryngospasm with
temporary drop in oxygen saturation, one patient required treatment for
sinus tachycardia, one patient developed bradyarrhythmia, and one
patient developed a pulmonary embolus after the fifth treatment. No
adverse events required patients to discontinue the study, thereby
enabling patients to continue treatment. Positive responses to the
treatments were seen in both treatment groups.
    Ghaziuddin et al. (Ref. 10) conducted a retrospective study of 16
adolescents treated for depression with ECT. Cognitive tests before ECT
treatment were compared to tests administered an average of 7 days
following completion of the ECT treatment (immediate testing) and again
at an average of 8.5 months following completion of ECT treatment. The
comparison of pre-ECT and the immediate post-ECT testing demonstrated
significant impairments of concentration and attention, verbal and
visual-delayed recall, and verbal fluency. A complete recovery of these
functions was noted in the cognitive testing conducted at 8.5 months.
There was no deficit in the ability to problem solve during the initial
or the subsequent testing. Cognitive parameters found to be impaired
during the first few days of ECT were recovered over several months
following the treatment. Therefore, there was no evidence of long-term
damage to concentration, attention, verbal and visual memory, or verbal
fluency. There were also no impairments of motor strength and executive
processing, even during the early (within 7 to 10 days) post-ECT
period.
    Considering the studies summarized above as well as the additional
literature referenced in the ECT public dockets and the deliberation of
the 2011 Panel, there is sufficient scientific evidence demonstrating,
with the establishment of special controls in combination with general
controls, a reasonable assurance of the SE for the use of ECT in
treating a severe MDE associated with MDD or BPD and safety for
treating catatonia in patients who are treatment-resistant or who
require a rapid response due to the severity of their psychiatric or
medical condition (see effectiveness of ECT for catatonia discussion in
following subsection). ECT in the indicated populations provides a
treatment option for serious diseases where other treatments are less
or minimally effective. Based on the totality of available evidence,
FDA has determined that the designated special controls mitigate the
risks associated with use of ECT in this patient population and provide
a reasonable assurance of SE.
2. Effectiveness of ECT for Catatonia
    The 2011 Panel was evenly split regarding their recommendation for
the reclassification of the use of ECT for catatonia. Several members
of the 2011 Panel who recommended class II for catatonia pointed out
that this psychiatric disorder is among the most severe and potentially
life-threatening and requires a rapid response.
    In the public comments in response to the proposed order, 24
published articles were submitted as attachments related to the use of
ECT for catatonia. Of these, 14 were published after FDA's systematic
literature review performed for the 2011 Panel meeting (Refs. 11-25).
As was the case at the 2011 Panel, there remain no randomized
controlled trials of ECT in catatonia. The articles published after the
2011 Panel are primarily case series reports, retrospective chart
reviews, and systematic literature reviews. All the studies reported on
patient outcomes, with the majority of studies reporting favorable SE
data.
    The systematic review from 2015 by Luchini et al. (Ref. 18)
identified 8 retrospective or observational studies that included at
least 10 or more subjects. Collectively, these 8 studies represented
346 catatonic patients who received ECT. Response rates ranged from 80
percent to 100 percent. Rates for adverse events were not provided, but
with regard to safety, the authors cite the transient cardiovascular
events that need to be monitored and managed, including parasympathetic
mediated bradycardia or temporary asystole and post-seizure sympathetic
stimulation that can lead to sinus tachycardia, bigeminy or trigeminy,
or ventricular arrhythmia in as many as 80 percent of patients with
known cardiovascular risk. Other risks are those associated with
administration of anesthesia in a catatonic patient. These side effects
are generally transient and resolve without adverse sequelae.
    A noteworthy series of the case series reports (Refs. 19 and 20)
all consistently found ECT to be very effective for the treatment of
catatonia with relatively few adverse events reported in the treated
patients. Given the clinical presentation of patients with catatonia,
including the lack of verbal and motor response due to the etiology of
the disease, the positive clinical outcome is unlikely to be
susceptible to placebo effects; therefore, FDA believes the well-
documented case series and open-label trials for the use of ECT in
catatonia support the recommendation to include catatonia in class II.
    The valid scientific evidence evaluated has enabled FDA to
determine that ECT for catatonia can be classified as class II because
general controls, in combination with special controls, are sufficient
to provide a reasonable assurance of SE. Based on a review of the
published literature to date, the recommendations from the 2011 Panel
meeting, and comments received in the ECT public dockets, FDA has
determined that sufficient evidence exists to establish special
controls and support a revision of the proposed classification of ECT
for the treatment of catatonia to class II. ECT for catatonia presents
the same types of risks to health and would be subject to the same
types of special controls identified for a severe MDE associated with
MDD or BPD in patients who are treatment-resistant or who require a
rapid response due to the severity of their psychiatric or medical
condition. Further, clinical guidelines for schizophrenia published in
2012 from the World Federation of Societies of Biological Psychiatry
(WFSBP) (Ref. 26) recommend consideration of ECT for catatonia as an
alternative when rapid resolution is necessary or when an initial trial
of benzodiazepines has failed. Therefore, instead of calling for PMAs
for ECT devices for the treatment of catatonia, FDA has satisfied the
requirements under section 515(i)(2) of the FD&C Act for revising the
proposed classification from class III to class II (special controls)
following reassessment of the published literature referenced in the
Executive Summary to the 2011 Panel, and comments and literature
received in the ECT public dockets.
3. Age Limitations on Adolescent Subpopulation for Use of ECT
    In the 2015 proposed order, FDA proposed that ECT devices should be
classified as class II (special controls) when used for treating adults
and adolescents 18 years and older with a severe MDE associated with
MDD or BPD, who are treatment-resistant or who require a rapid response
due to the severity of their psychiatric or medical

condition. In response to the proposed order, public comments included
submission of 29 articles regarding the use of ECT in children and
adolescents. Some of these comments recommended the age for using ECT
should be lower than 18 years of age. Half of these articles (Refs. 13-
17, 21, 25 and 27-31) were published after the 2011 meeting. Articles
published after the 2011 Panel meeting included children and
adolescents with a variety of psychiatric conditions, including
catatonia, a severe MDE associated with MDD or BPD and childhood
schizophrenia.
    Because the current labeling of legally marketed ECT devices does
not include specific age limitations for any indication within the
scope of this classification and FDA received public comments
advocating expansion to include the adolescent age range, FDA believed
it was important to reassess the evidence and conduct a systematic re-
review of valid scientific evidence for the use of ECT in catatonia or
a severe MDE associated with MDD or BPD in different age groups.
Accordingly, similar to the treatment of catatonia, FDA conducted a
reevaluation of the SE of ECT for use in the adolescent subpopulation
by reassessing the published literature referenced in the Executive
Summary to the 2011 Panel, and in comments and literature received in
the ECT public dockets relating to the adolescent age range for using
ECT under section 515(i)(2) of the FD&C Act. Unlike the evidence
reported for the adolescent population, limited experience and only a
few isolated reports were available for patients less than or including
12 years of age. Therefore, this age range was not re-evaluated.
    With regard to safety of ECT in treating catatonia or a severe MDE
associated with MDD or BPD, specifically in individuals under the age
of 18, Jacob et al. (Ref. 17) conducted a 10-year retrospective chart
review of all adolescents and children who had received at least one
session of ECT therapy in the Child and Adolescent Psychiatry Centre,
National Institute of Mental Health and Neurosciences. Twenty-two
patients, most who were severely ill, received therapy in the 10-year
window. In this group, the majority of patients had no adverse effects;
four patients (18.4 percent) experienced headache immediately after the
ECT procedure, and three of eight monitored patients had prolonged
seizures (greater than 2 minutes). At discharge, approximately 80
percent were rated as ``much improved'' or ``very much improved'' based
on the Clinical Global Impressions-Improvement (CGI-I) scale.
    Cohen et al. (Ref. 32) investigated cognitive impairment at long-
term followup in adolescents treated with ECT for severe mood disorders
and compared the neuropsychological test results of the ECT-treated
subjects with psychiatric comparison subjects matched for sex, age, and
diagnosis. This study found that cognitive test scores of the subjects
treated with ECT were similar to those subjects who did not receive
ECT. In the ECT treated group 6 of the 10 subjects reported having had
memory losses immediately after ECT treatment and 1 reported long-term
subjective memory impairment. In the long-term followup study (3.5
years average), the cognitive tests of anterograde memory in the ECT
treated group showed no measurable difference compared to the matched
group.
    A systematic review by Lima et al. (Ref. 28) published in 2013
found 212 published studies on the use of ECT in children and
adolescents. Of these, 39 studies met the authors' criteria for
inclusion in their systematic review. The reviewed studies specified
indications of ECT use in adolescents, evaluated the effectiveness of
this therapy in producing remission, and explored the potential risks
and complications of the procedure. Overall, the results of this
systematic review found that the use of ECT in adolescents is
considered a highly effective option for treating several psychiatric
disorders including MDE and catatonia, achieving high remission rates,
and presenting few and relatively benign adverse effects. These authors
conclude that the risks to adolescents can be mitigated by the correct
use of the technique and are considered minimal when compared to the
treatment benefit.
    Consoli et al. (Ref. 33) investigated the use of ECT in adolescents
with a primary diagnosis of catatonia. These authors reviewed the
published literature (1985-2009) on the use of ECT in child and
adolescent patients with catatonia. In their meta-analysis of studies
that included 10 patients or more, only 1 study of 12 patients included
subjects below the age of 13 (it included patients in the age range of
12 to 18). This review found that ECT is used as a second-line
management after high-dose benzodiazepine trials and that ECT is an
effective, safe, and useful procedure in the treatment of catatonic
adolescents (n=59).
    The largest systematic review of the use of ECT in young people was
reported by Rey and Walter (Ref. 34). This 1997 review assessed 60
studies comprising nearly 400 patients, with the majority of patients
between the ages of 13 and 18 years and found rates of improvement
across studies, including 63 percent for depression and 80 percent for
catatonia. Serious complications were very rare, whereas minor,
transient side effects appeared common. These authors concluded that
ECT in young people appears to be similar in SE to that found in
adults, but note that these results are limited by the lack of
controlled clinical trials.
    FDA's review of other retrospective studies submitted as comments
to the proposed order have found similar results. Walter and Rey (Ref.
35) studied 42 patients aged 14 to 18 with a variety of psychiatric
diagnoses who received ECT therapy and observed marked improvement or
resolution of symptoms in about half of the patients who completed the
therapy. Ghaziuddin et al. (Ref. 36) observed clinically significant
improvement in 11 of 11 adolescent patients in the 13- to 18-year range
with major depressive episode. Of these 11 adolescents 7 achieved
euthymia, which is defined as a Children Depression Rating Scale-
Revised (CDRS-R) of 40 or less. Strober et al. (Ref. 37) reviewed the
treatment of 10 adolescents (13-17 years) with major depression or BPDs
and observed complete remission in 6 patients and partial remission in
the other 4. Cohen et al. (Ref. 38) studied 21 adolescents (age 14-19)
and observed 100 percent response in major depression and 75 percent
response in bipolar-mania. In one of a few studies with a control arm,
Kutcher and Robertson (Ref. 39) studied 32 bipolar patients and
compared 16 subjects who received ECT to 16 (serving as controls) who
were offered ECT but refused it. The ECT group improved significantly
more than the group who did not receive ECT and the duration of their
hospitalization was cut in half (74 vs. 176 days on average). Taken as
a whole, these reports are consistent in reporting effectiveness of ECT
in treating depressive episodes and catatonia in young adolescents.
    In addition, the American Academy of Child and Adolescent
Psychiatry (AACAP) has published guidelines for the use of ECT in
adolescents and children. In the AACAP publication on practice
parameters (Ref. 40), they reviewed selected publications since 1990.
While the use of ECT in adolescents is uncommon within the age of 13 to
17 (representing about 1.5 percent (Ref. 40) of the total population of
individuals who receive ECT), the benefits of therapy are acknowledged.
This publication also indicates that while the use of ECT in patients
12 years of age or younger is rare and necessitates further study, the
guidelines identify risk mitigations of

the technique. Overall the AACAP recommends that patients 13 years of
age and older are appropriate for considering use of ECT in treating
catatonia or a severe MDE associated with MDD or BPD.
    While the discussion at the 2011 Panel meeting of ECT use in
treating adolescents with catatonia or a severe MDE associated with MDD
or BPD was limited, the 2011Panel did hear and discuss comments during
the open public hearing both on adolescent age groups as well as
considerations as it relates to ECT (Ref. 41). Although a primary
emphasis was upon adult populations towards the conclusion of the 2011
Panel proceedings, sufficient and compelling discussion was heard
regarding adolescent response to ECT, especially during the opening
public hearing comments. In summary, there was the 2011 Panel
discussion focused on adolescent patient use of ECT, as well as many
comments including literature references addressing inclusion and
exclusion on the basis of age for specific indications for use of ECT
(e.g. schizophrenia, bipolar manic states, schizoaffective disorder,
and schizophreniform disorder).
    Additionally, FDA conducted a review of the MAUDE database from
August 2016 to December 2017. The additional MDRs from the MAUDE
database do not appear to be significantly different from those
compiled for the 2011 Panel meeting and the small number of MDRs is
consistent with the safety record reported in the literature for ECT.
    As stated previously, FDA has reevaluated the valid scientific
evidence for use of ECT in treating adolescents and, in the case of
catatonia or a severe MDE associated with MDD or BPD, we believe the
requirements under section 515(i)(2) of the FD&C Act for revising the
classification of the age limitation for the adolescent subpopulation
are satisfied. Based upon the assessment of the totality of evidence,
FDA believes that special controls, along with general controls, can
provide a reasonable assurance of SE of the use of ECT for all
adolescent age groups (13-21 years) and, therefore, is modifying the
designation for class II for the indications of catatonia or a severe
MDE associated with MDD or BPD in the adolescent subpopulation to
include individuals 13 years and older who are treatment resistant or
require a rapid response.
4. Effectiveness of ECT for Schizophrenia, Schizoaffective Disorder,
and Mania
    During the 2011 Panel meeting, members expressed diverse opinions
on the effectiveness of ECT for treatment of schizophrenia,
schizoaffective disorders, and mania, but the majority of the 2011
Panel members supported class III designation for these indications. A
number of published articles on the use of ECT to treat schizophrenia
and schizoaffective disorder were submitted and reviewed as attachments
to the ECT public dockets. Of these, approximately 15 were published
after the 2011 Panel meeting. The majority of these articles published
after the 2011 Panel meeting review were either isolated case reports
or retrospective chart reviews. SE data, including clinical outcomes,
for both adults and adolescents with a primary diagnosis of
schizophrenia or schizoaffective disorder (Refs. 14, 23, 30, 42, and
43-47) resulted in variable patient outcomes, while mania had more
positive outcomes. However, the available evidence across patients for
these conditions was limited when compared to the available evidence
for other conditions presented in this final order for which class II
is designated.
    There was one published practice guideline (Ref. 48) that provided
updated treatment recommendations for the acute treatment of
schizophrenia and the management of treatment resistance. This
guideline concludes that there is limited evidence for general efficacy
of ECT in treatment-resistant schizophrenia, but that in certain cases
ECT as an adjunct to antipsychotic therapy may be appropriate. This is
in contrast to the guideline recommendation for catatonia where ECT is
considered an important therapeutic alternative (see above discussion
in section III.A.2, Effectiveness of ECT for Catatonia).
    Iancu et al. (Ref. 44) conducted a retrospective chart review of 20
consecutive patients with schizophrenia or schizoaffective disorder who
were individually treated with at least 30 ECT sessions at the Tel Aviv
University. All of these patients had been hospitalized for most or all
of the previous 3 years. In this group of chronically hospitalized
patients, the authors conclude that ECT treatment improves general
function and reduces verbal aggression and self-harm. This patient
group had a mean age of 65 and the average age at disease onset was 22
years. Patients were selected for treatment based on inadequate
response to medications, history of a good response to ECT in the past,
aggression, self-injury, and refusal to eat or drink. Improvement was
seen on all assessed scales including the Global Assessment of
Functioning, Clinical Global Impression-Severity and Overt Aggression
Scale but most changes before and after ECT were not clinically
meaningful or statistically significant.
    Kristensen et al. (Ref. 45) reviewed the treatment of 72
consecutive hospitalized patients between 2003 and 2008 from two
hospitals in the Copenhagen area. Fifty-five had a diagnosis of
schizophrenia and 17 a diagnosis of schizoaffective disorder. All
patients had been hospitalized for at least a week and the indication
for ECT was an increase in acute episodes or symptom severity leading
to hospitalization. The patient ages ranged from 18 to 79 and the
disease duration ranged from 1 to 40 years. The duration of the
patients' psychotic behavior ranged from a few weeks to over 5 years.
ECT was effective in this severely ill population as reflected by a
measure of relief from psychosis and disruptive behavior as described
in the patient charts. Using information about the size of the
catchment area for the involved hospitals, the authors were able to
estimate that only about 1.5 percent of patients with schizophrenia
received ECT over the 6-year study period in this area of Copenhagen.
Because this represents a select and small fraction of the population
with schizophrenia, it is not possible to generalize these results to
the general population of schizophrenic individuals.
    Petrides et al. (Ref. 47) studied patients with clozapine-resistant
schizophrenia in a single-blind study where 20 clozapine-resistant
patients received ECT as an adjunct to the clozapine treatment and 19
received usual (clozapine) care. Response was defined as a 40 percent
or greater reduction in symptoms based on the psychotic symptom
subscale of the Brief Psychotic Rating Scale, a Clinical Global
Ratings-Severity (CGI-S) rating of less than 3, and a CGI improvement
rating less than or equal to 2 following an 8-week course of treatment.
Fifty percent of patients in the treatment group that received the ECT
met the response criteria compared to none of the patients in the
control group. FDA believes that these results, while promising, have
significant limitations. The Denmark Study represents a population of
hospitalized patients who may not be representative of the general
population of schizophrenic individuals. The Petrides study was small
and focused on the subpopulation of clozapine resistant patients and
again cannot be

extrapolated to the general schizophrenic patient population. The
available valid scientific data on the schizophrenic patient population
are limited and insufficient to demonstrate that the use of ECT in
schizophrenia patients can be safe and effective with the use of
special controls.
    Other studies have focused on the use of maintenance ECT in the
treatment of patients with schizophrenia and schizoaffective disorders
(Refs. 23, 27, and 46). In each of these studies, the patient
populations are highly selected and represent a small minority of the
schizophrenic or schizoaffective populations. Also, a number of
additional therapies were given to patients, with limited use of ECT in
some cases. While the results are promising in these selected patient
populations, the evidence available is limited. Moreover, practice
guidelines have not called out schizophrenia and schizoaffective
disorders for treatment with ECT. With limited data on different select
subpopulations, FDA believes that there is insufficient evidence, at
this time, to establish special controls for the subpopulations that
might benefit from the treatment. Therefore, FDA believes that the use
of ECT to treat schizophrenia or schizoaffective disorder is
appropriately currently regulated in class III.
    Ten published articles were submitted to the ECT public dockets
regarding the SE of ECT for mania. All the articles were published
prior to the 2011 Panel meeting and no ``new information'' on the SE of
mania was submitted to the ECT public dockets that were not available
to the 2011 Panel. In reviewing the ECT public dockets, FDA did not
identify additional scientific information since the 2011 Panel meeting
supportive of reclassifying mania to class II. The published reports on
using ECT for the treatment of mania are relatively few, have small
numbers of patients, and acknowledge that there are viable alternative
treatments in this population.
    In one study, Black et al. (Ref. 49) systematically reviewed
records of patients treated with ECT for mania or depression over a 12-
year period at the University of Iowa Hospital Center. Patient outcome
was divided into five categories based on patient discharge notes with
the category ``marked improvement'' applied to patients where the
discharge notes suggested there was complete resolution of depressive
or manic symptoms. In this review, there was marked improvement in a
substantial majority of the patients with depression and with mania.
However, the total numbers of patients treated included 422 patients
treated for depression but only 37 patients treated for mania. As a
result of the differences in numbers of patients treated, there is
greater uncertainty in the significance of this retrospective study in
mania compared with depression.
    Mukherjee et al. (Ref. 50) reviewed the treatment of 30 manic
patients at a psychiatric institute in India treated for mania with
ECT. They observed remission of mania in 26 of 30 patients. Results are
confounded though by the concurrent prescription of neuroleptics at the
time of admission for treatment.
    Small et al. (Ref. 51) compared ECT with lithium maintenance
therapy to lithium treatment in 34 patients hospitalized for mania.
Although the patients who underwent ECT improved more than the lithium
treatment patients during the first 8 weeks, the study found no
differences in clinical ratings after 8 weeks and no differences in
rates of relapse, recurrence, or re-hospitalization in the followup
period, when compared to pharmacotherapy.
    FDA concluded that based on the published literature referenced in
the Executive Summary to the 2011 Panel, comments and literature
received in the ECT public dockets, the small number of patients
treated and limited outcomes reported, the existence of confounding
factors in studies, and the availability of alternative therapies with
similar reported effectiveness, that special controls cannot be
established to provide a reasonable assurance of SE, and, therefore, it
is appropriate to maintain ECT to treat mania in class III.

B. Comments on Reclassifying ECT Based on Safety and Effectiveness

    In this section, comments regarding the SE of ECT are categorically
grouped together so that FDA's responses could be addressed by topic
instead of each comment considered independently.
    (Comment 3) Several comments indicated that ECT was not safe and/or
not effective, particularly in the long term. Several comments noted
that ECT had not been used safely and/or effectively in their practice,
or on themselves as a patient, or on a family member or a friend.
Several comments stated ECT injures patients and is not therapy.
Several comments also noted long-term memory, cognitive, or functional
impairment following ECT administration. Instead of using ECT, several
comments recommended alternative treatments, including acupuncture,
transcranial magnetic stimulation, or nutritional or solar therapy.
    (Response 3) Comment 3 reflects significant concern on the part of
some patients and caregivers about the risks of ECT. Table 1 shows how
FDA believes that the risks to health associated with ECT for treatment
of catatonia or a severe MDE associated with MDD or BPD can be
mitigated by the designated special controls.

   Table 1--Identified Risks to Health and Mitigation Measures for ECT
------------------------------------------------------------------------
       Identified risks to health             Mitigation measure(s)
------------------------------------------------------------------------
Adverse reaction to anesthetic agents/   Labeling
 neuromuscular blocking agents.
Adverse skin reactions.................  Biocompatibility Labeling
Cardiovascular complications...........  Labeling
Cognitive and memory impairment........  Technical parameters, Non-
                                          clinical test data, Labeling
Death..................................  Labeling
Dental/oral trauma.....................  Labeling
Device malfunction.....................  Performance data,
                                          Electromagnetic compatibility,
                                          Software verification,
                                          validation, and hazard
                                          analysis
Manic symptoms.........................  Labeling
Pain/discomfort........................  Labeling
Physical trauma........................  Labeling
Prolonged or tardive seizures..........  Labeling
Pulmonary complications................  Labeling
Skin burns.............................  Performance data, Labeling
Worsening of psychiatric symptoms......  Labeling
------------------------------------------------------------------------

    FDA acknowledges that the individuals for whom ECT therapy may be
prescribed are at significant risk for complications including death
from their underlying conditions. Milstein et al. (Ref. 52) completed a
retrospective study of 1,494 psychiatric subjects followed for 5 to 7
years following hospitalization for a psychiatric condition. They found
76 deaths in this group of patients with 16 of the deaths being by
suicide. In this group, ECT was not protective but also did not
increase the risk for death. Labeling will be required to explain the
potential risks and benefits to ensure that patients, caregivers, and
family members understand the magnitudes of the risks and the benefits
of ECT. FDA acknowledges the important role of patient preference and
patient choice in selecting treatments. Patient preference is important
in balancing the individuals' assessment of risk and benefit,
especially in the presence of serious and potentially life-threatening
disorders. This classification is concerned with the use of ECT for
certain specified uses and does not address the potential use of other
treatments that patients may consider. FDA believes that for certain
indications, special controls as established in this final order, along
with general controls, provide a reasonable assurance of SE of ECT by
mitigating the identified risks to health. As such, FDA disagrees with
the comments that ECT should not be reclassified for any indications to
class II.
    FDA reclassifies devices under section 515(i)(2) of the FD&C Act in
accordance with the criteria in section 513(a) of the FD&C Act. The
primary purpose of reclassification is to apply the appropriate level
of regulatory controls for a device based on the most current
information regarding its SE. FDA notes that reclassification does not
imply that ECT is a preferred form of treatment. FDA recommends that
patients consult with their healthcare providers to determine if ECT is
the best treatment option for them or if there are suitable alternative
treatments. FDA notes that the patient labeling is required to list
alternative treatments (see Sec.  882.5940(b)(1)(ix)(E) (21 CFR
882.5940(b)(1)(ix)(E))).
    (Comment 4) Some comments stated that FDA did not consider animal
studies and death data in proposing to reclassify these devices.
    (Response 4) FDA does not agree with these comments. Information
about adverse events, including death, was carefully considered
regarding the reclassification action. Section 4.8 of the safety review
in the FDA Executive Summary prepared for the 2011 Panel meeting
specifically addresses the risk of death. Data for deaths from MDR
analyses was also considered and made part of the risks identified in
the proposed order. FDA acknowledges that there is uncertainty in the
estimate of risk of death from these sources of information and that
the risks are likely changing as a result of evolution in the practice
of medicine. In light of this risk, the labeling is required to include
death (Sec.  882.5940(b)(1)(ix)(H)(3)(viii)) as a risk of the use of
ECT. In some cases where human experience is limited, animal studies
can be of significant value in predicting outcomes in humans.\2\
However, in this case where there is a significant and substantive
experience with the use of these devices to treat humans, FDA believes
that the human study data are the primary sources for review and
consideration.
---------------------------------------------------------------------------

    \2\ FDA supports the principles of the ``3Rs,'' to reduce,
refine, and replace animal use in testing when feasible. We
encourage sponsors to consult with us if it they wish to use a non-
animal testing method they believe is suitable, adequate, validated,
and feasible. We will consider if such an alternative method could
be assessed for equivalency to an animal test method.
---------------------------------------------------------------------------

    (Comment 5) Several comments opposed the reclassification saying
that ECT should remain in class III for all indications. Several
comments indicated that current safety or effectiveness information was
insufficient to ensure patient protection. Several comments indicated
that proof of SE should be required before the device enters the
market. Several comments indicated that the 510(k) clearance pathway
was not sufficient for ECT devices.
    (Response 5) FDA disagrees with these comments that ECT should not
be reclassified to class II as specified in this final order for
certain indications. 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 SE.
Based on FDA's independent review of the scientific evidence, FDA has
determined that the special controls established in this final order,
including performance data, technical parameters of the device, and
extensive labeling requirements, along with general controls, can
provide reasonable assurance of SE of ECT for the specified class II
indications. ECT devices for indications in class II will require a
510(k) (or an amendment to a previously cleared 510(k) if already
legally marketed) that demonstrates compliance with these special
controls. ECT devices for indications other than those being classified
into class II will require premarket approval as insufficient evidence
currently exists to establish adequate special controls for these uses.
    (Comment 6) Several comments indicated that ECT did not treat the
biological basis of depression or other mental disorders. Several
comments indicated that electricity did not treat the underlying
cause(s) and could exacerbate mental disorders. Several comments
indicated that there is no evidence that mental disorders are
neurobiological. Several comments indicated that ECT may be used in
patients who are misdiagnosed.
    (Response 6) For a device to be determined to have a reasonable
assurance of SE, FDA evaluates the device's performance outcomes
relative to the indications for use and not necessarily the
mechanism(s) of action of the device, which may not be well understood
in some cases. For ECT, the clinical data reflecting the device's
performance in relation to the indications for use have been discussed
above in response to Comment 2. Additionally, knowledge of the
underlying causes of mental disorders is not required to evaluate a
reasonable assurance of the SE of a device type for a specified
intended use. Therefore, the biological basis or cause of the
underlying mental disorder is outside of the scope of this
reclassification.
    (Comment 7) Several comments suggested that reclassification would
increase acceptance of ECT. Several comments indicated that ECT is not
as safe or effective when compared to other available treatments.
Several comments opposed the reclassification saying that
reclassification indicated that ECT is a preferred method of treatment.
    (Response 7) The primary purpose of reclassification is to apply
the appropriate level of regulatory controls for a device type based on
the ability to reasonably assure SE. FDA notes that reclassification
does not imply that ECT is a preferred form of treatment. This order is
neither a recommendation of ECT treatment nor a determinant of whether
ECT is safer or more effective than alternative treatments. The purpose
of the proposed and final order process is to identify the regulatory
controls necessary to reasonably assure SE for ECT and to provide the
evidence supporting this determination. Based upon FDA's assessment,
special controls, in combination with general controls, are necessary
and sufficient to provide a reasonable assurance of SE for the use of
ECT in treating catatonia or

a severe MDE associated with MDD or BPD in patients age 13 years and
older who are treatment-resistant or who require a rapid response due
to the severity of their psychiatric or medical condition. ECT devices
for indications other than those identified in the previous sentence,
including schizophrenia, schizoaffective disorders, schizophreniform
disorder, bipolar manic states, and catatonia or a severe MDE
associated with MDD or BPD in patients under 13 years or patients 13
years or older who are not treatment-resistant or who do not require a
rapid response due to the severity of their psychiatric or medical
condition, will require premarket approval. FDA believes that
insufficient evidence currently exists to establish special controls to
mitigate the risks to health and provide a reasonable assurance of SE
for those uses.
    (Comment 8) Several comments indicated that ECT should be banned.
Several comments characterized ECT as inhumane. Commenters indicated
that the United Nations Special Rapporteur on Torture and Other Cruel
Inhuman or Degrading Treatment or Punishment February 16, 2013, defined
ECT without consent as torture.
    (Response 8) FDA disagrees that ECT should be banned. Section 516
of the FD&C Act (21 U.S.C. 360f) authorizes FDA to ban a device when,
based on all available data and information, FDA finds that the device
``presents substantial deception or an unreasonable and substantial
risk of illness or injury.'' During review of the scientific evidence,
FDA did not identify sufficient evidence to ban ECT. FDA determined
that special controls, in combination with general controls, can
mitigate the identified risks of ECT for certain intended uses and
mitigate risks associated with ECT use. FDA determined that there is a
reasonable assurance of SE for ECT treatment for the identified
indications for use and patient populations. Therefore, FDA has
determined that ECT does not present substantial deception or an
unreasonable and substantial risk of illness or injury.
    As noted, we acknowledge the February 1, 2013, United Nations
Report of the Special Rapporteur on torture and other cruel, inhuman or
degrading treatment or punishment by Juan E. M[eacute]ndez does
recommend banning the administration of non-consensual electrical
stimulation against persons with disabilities (Ref. 53). Persons with
disabilities include persons with long-term intellectual or sensory
impairments. The report does not address the use of electrical
stimulation to treat conditions such as a severe MDE associated with
MDD or BPD, schizophrenia, bipolar manic states, schizoaffective
disorder, schizophreniform disorder, or catatonia. As noted in the
proposed order and adopted in this final order, appropriate directions
for use and specific labeling special controls (Sec.
882.5940(b)(1)(viii) and (ix)) are required for the safe use of ECT.
    (Comment 9) Several comments were concerned that reclassification
would make it easier for either healthcare professionals or non-
healthcare professionals to overly or inappropriately use ECT. Comments
indicated that ECT may be used to shorten hospital stays without regard
for patient outcomes. Comments indicated that ECT may be used to
control patients or reduce unwanted behavior such as screaming rather
than as treatment for a medical condition. Several comments questioned
the regulation of ECT use in other indications not included in class II
in the split classification.
    (Response 9) FDA does not regulate the practice of medicine (see
section 1006 of the FD&C Act (21 U.S.C. 396)). Diagnosis and treatment
of patients are clinical decisions that fall within the practice of
medicine. Rather, FDA regulates the use of a device as indicated by the
person or entity offering the device for interstate commerce. The
classification of indications for use for ECT devices are specified in
the identification language in the codified classification regulation
(see Sec.  882.5940). Through the classification process, FDA has
determined the level of regulatory control necessary to provide a
reasonable assurance of SE of ECT devices for these indications. ECT is
a prescription only device that is not safe for use except under the
supervision of a practitioner licensed by law to direct the use of the
device and for which prescription labeling requirements must be met
(see 21 CFR 801.109). The labeled uses of the device must conform to
the indications that have been cleared or approved by FDA through the
premarket review process. FDA does not regulate off-label use of ECT by
physicians.

C. Comments on Patient Concerns

    In this subsection, comments on patient concerns with using ECT are
categorically grouped together so that FDA's responses could be
addressed by topic instead of each comment considered independently.
    (Comment 10) Several comments state that FDA's call for PMA
applications is disingenuous because PMA applications have not been
required for ECT devices since they were originally classified.
Comments indicate that because the proposed order states ECT devices
for some indications will be in class II, device manufacturers will not
have an incentive to apply for additional indications through the PMA
process, because, under the practice of medicine, healthcare
professionals can use class II ECT devices for indications beyond those
cleared via 510(k) for indications that are in class III.
    (Response 10) FDA disagrees with these comments. Finalizing the
classification of ECT includes a requirement that PMA applications be
submitted prior to marketing of ECT devices for indications other than
those identified as class II within this final order, and it is the
responsibility of the manufacturer to ensure that a PMA application is
submitted in such circumstances. However, FDA is not permitted to limit
or interfere with the authority of a healthcare professional to
administer any legally marketed device to a patient for any condition
or disease within a legitimate clinician-patient relationship.
    (Comment 11) Several comments raised concerns about a split
classification and the conditions under which devices could be used
under either classification. Several comments indicated that a split
classification could restrict the use of ECT for indications not
included in class II and thereby limit treatment options for patients.
Comments asked if there is evidence of patients not receiving treatment
when ECT devices are in class III. Comments asked for guidance on
whether class II ECT devices can be used on patients with a severe MDE
associated with MDD accompanied by another condition. Comments also
stated concern that class II ECT devices will be used as predicate
devices for other devices with different current or voltage strength,
or different pulse length, pattern or waveform, saying such differences
could impact safety including cognitive side effects and/or
effectiveness of ECT treatment.
    (Response 11) FDA's reclassification of ECT to class II for the
indications specified in the final order is an effort to make ECT
available for the benefit of patients with conditions for which general
and special controls can provide a reasonable assurance of SE. For
these indications, sufficient scientific evidence exists for FDA to
establish special controls that, in combination with general controls,
provide reasonable assurance of SE of ECT. For other indications,
sufficient scientific evidence does not currently exist to be

able to establish special controls to mitigate the risks to health at
this time. The indications for which there is currently insufficient
evidence to develop special controls will remain class III and require
a PMA pursuant to section 513(a)(1)(C) of the FD&C Act. Because of the
differing levels of scientific evidence currently available to
establish special controls for the various uses of ECT, a split
classification was warranted in this case. If warranted by new
scientific evidence, FDA could reclassify ECT for other indications to
class II in the future.
    Under section 1006 of the FD&C Act, FDA is prohibited from
interfering with the authority of a healthcare professional to
prescribe or administer any legally marketed device to a patient within
a legitimate clinician-patient relationship. As such, FDA does not
regulate the practice of medicine. Rather, FDA regulates the use of a
device as indicated by the person or entity offering the device for
interstate commerce. The indications for which FDA has determined ECT
devices have a reasonable assurance of SE based on the general controls
and the identified special controls are in the codified classification
regulation (see Sec.  882.5940). Once a product is approved or cleared,
a healthcare professional is able to prescribe the device based on a
patient's condition. ECT is a prescription device and FDA relies on
licensed practitioners to direct its use. Treatment of patients remains
under the clinical discretion of their healthcare practitioner. While
treatment of patients falls under the practice of medicine, healthcare
professionals should carefully consider all ECT device labeling,
including potential adverse events, warnings, and medical conditions
that can increase patient risk when deciding if ECT is appropriate for
their patients, including those with comorbid conditions. The
healthcare professional is responsible for providing appropriate
ongoing medical management to mitigate any patient specific risks
associated with comorbid conditions.
    If ECT devices are used as predicate devices for subsequent ECT
devices, any differences in the technical parameters (e.g., waveform,
output mode, pulse duration, maximum charge, and energy as identified
in Sec.  882.5940(b)(1)(i)) between the predicate device and the new
device must be characterized and will be considered as part of FDA's
substantial equivalence determination to ensure that such differences
do not raise different questions of SE.
    (Comment 12) Several comments were concerned that adequate, well-
informed consent may not take place prior to ECT treatment. Several
comments indicated concern over the use of ECT without consent or
without full disclosure of risks. Several comments were concerned with
involuntary treatment and its outcomes. Comments indicated that
conversations about potential benefits, potential risks, alternative
treatments, and the typical experience and course of ECT treatment
should occur over several sessions prior to ECT treatment. Comments
asked that FDA provide additional guidance and recommendations to
healthcare professionals on the procedures for informing patients and
on obtaining written informed consent from patients or their legally
authorized representatives prior to ECT treatment. Comments indicated
that family members or other caregivers should be included in the
informed consent process and should provide input on how the patient is
responding to ECT treatment including any adverse events. Several
comments indicated that ECT should only be used in settings of formal
informed consent, such as with a documented checklist or when it is
specified in a psychiatric advance directive. A comment suggests that
FDA develop a patient decision aid related to ECT that considers key
clinical variables and alternative therapeutic options as well as
incorporating patient values, concerns, and preferences. Several
comments indicated that the order should specify that consent is an
ongoing process, that information should be provided throughout
treatment, and that at any time during the course of ECT treatment,
patients can request that treatment be stopped and can withdraw consent
for further treatment. Several comments indicated that some patients
may not be able to give consent due to their medical condition.
    (Response 12) These comments are focused on how patients are
informed about the risks, benefits, and alternatives to ECT. FDA agrees
that ECT informational material, including information about benefits
and risks, should be discussed with the patient and, if applicable,
with a designated family member or other individual. In Sec.
882.5940(b)(1)(ix), FDA requires that certain information be provided
in the patient labeling for a class II ECT device. The appropriate
treatments for a patient with catatonia or a severe MDE associated with
MDD or BPD is a complex matter that requires the supervision of a
practitioner licensed by law to direct the use of the device. In
selecting the appropriate treatment, the practitioner should consider
many factors, such as the patient's medical history and the severity of
their psychiatric or medical condition. FDA believes that the device
labeling required per the special controls will provide patients and
healthcare professionals with information that will improve their
understanding of the ECT device and assist in selecting the appropriate
treatment for patients. ECT is a prescription device, and FDA and
licensed practitioners are relied upon to direct its use.
    Informed consent procedures may differ across each State agency,
institution, hospital, clinic, and practice. For ECT treatment, FDA
expects review boards and State agencies to have the appropriate
requirements for medical professionals to provide the appropriate
informed consent to patients and family members, and to take action
when necessary. The patient labeling is required to include information
on ECT use, potential benefits, warnings regarding risks of ECT, and
alternative treatments. The information required in the patient
labeling will help patients make an informed decision about ECT
treatment. Patients may also discuss ECT and other treatment options
with their healthcare professionals, family members, or other
individuals. Patients, or their legally authorized representative, may
withdraw consent and request that ECT treatment be stopped at any time.
    According to the Surgeon General, involuntary ECT treatment is
uncommon in the United States. In every State in the United States, the
administration of ECT on an involuntary basis requires a judicial
proceeding (Ref. 54). At this time, FDA declines to recommend the
development of patient decision aids related to ECT that considers key
clinical variables and alternative therapeutic options as well as
incorporating patient values, concerns, and preferences. FDA is
concerned that including such information may be more confusing than
helpful given the complexity of treating a number of different
psychiatric disorders. FDA also requires patients consult a
practitioner licensed by law to administer or use the ECT device.
    (Comment 13) Several comments indicated training or education
should be required for healthcare professionals to be eligible to
administer ECT. Several comments indicated that the order should
specify what type of healthcare professional should be able to
administer ECT. Several comments indicated that healthcare
professionals

other than physicians should be able to administer ECT.
    (Response 13) FDA is in agreement that there is a need for ongoing
training for healthcare professionals who administer ECT. ECT is a
complex procedure that requires specialty training for reasonably safe
and effective administration. As stated in the proposed order and
adopted in this final order, FDA is requiring device labeling to
specify the clinical training that is needed by those using the ECT
device to ensure appropriate use and appropriate ongoing medical
management of the patient.
    (Comment 14) Several comments indicated that those who administer
and/or study ECT have conflicts of interest. Several commenters noted
that the doctors recommending ECT treatment profit financially from
administering ECT. Commenters asked if FDA considers possible conflict
of interests for researchers when assessing the validity of ECT
research used to support the reclassification.
    (Response 14) The potential for conflict of interest of healthcare
professionals administering ECT is outside the scope of this final
order and does not bear upon FDA's careful evaluation of the valid
scientific evidence on the SE of ECT. FDA's Federal conflict of
interest provisions are directed toward the potential for conflict of
interest on the part of FDA employees and outside experts used on FDA's
advisory committees (see 5 CFR 2640 and 18 U.S.C. 208).
    FDA defines valid scientific evidence in Sec.  860.7(c)(2).
Isolated case reports, random experience, and unsubstantiated opinions
are not regarded as valid scientific evidence. In standard clinical
practice as in ECT treatment, healthcare professionals are compensated
for providing treatment to patients. Institutional review boards assess
potential conflicts of interest for healthcare professionals conducting
clinical research on ECT. Under 21 CFR part 54, FDA assesses potential
financial conflicts of interest for healthcare professionals conducting
clinical research on ECT. Scientific journals typically require
disclosure of funding and potential conflicts of interest when
publishing research findings.
    (Comment 15) Several comments were concerned about the benefit-risk
ratio for ECT treatment. Comments raised concerns that the risks of ECT
may be higher in vulnerable populations, including the elderly, who
could have hemorrhaging from increased intracranial pressure, pregnant
women, and patients with multiple disorders, cancer, or multiple
medications. Comments indicated that the risks of ECT are higher than
acknowledged because adverse reactions are mischaracterized so that
they are not associated with ECT. Comments also expressed concern that
patient-reported outcomes differ from reported adverse events and study
outcomes. Comments said some adverse effects of ECT, such as emotional
trauma, have had limited scientific study but are evidenced by many
subjective patient accounts and should be considered further. Comments
noted that the benefit-risk ratio could change over the course of an
ECT treatment. Comments said the benefit could decrease and the risks
could increase because higher stimulation is needed for effectiveness
over the course of treatment, leading to a higher risk of adverse
events. In addition, comments said the repeated use of general
anesthesia for ECT over a relatively short period of time could
increase the risk of side effects.
    (Response 15) FDA believes there is reasonable assurance that with
the special controls codified in the final order, in combination with
general controls, the benefit of ECT outweighs the risk for the
indicated populations whose condition is treatment-resistant or who
require a rapid response due to the severity of their psychiatric or
medical condition. The practitioner administering ECT is responsible
for ongoing medical management and disclosure of changes in the risks
for individual patients during a course of ECT treatment. In
considering the benefits and risks, FDA took into consideration all
available information, including the existing published scientific
literature, practice guidelines published by major psychiatric and lay
mental health organizations, input from the external classification
panel, and reports of adverse events contained in the MAUDE database.
Based upon all of this information, FDA has determined that the
probable benefits to health from use of the device outweigh the
probable risks for the class II indications and, furthermore, the risks
associated with the use of ECT for the class II indications can be
mitigated with the proposed special controls.
    (Comment 16) Several comments indicated that the special controls
were inadequate to properly mitigate severe risks such as the risk of
cognitive impairment and death. Comments indicated that special
controls cannot be developed for unknown risks. For example, it is not
known whether ECT patients return to baseline memory functioning after
6 months. A comment asserts that FDA must use scientific evidence to
evaluate risk to memory and it is not enough for FDA ``to believe'' the
potential benefits of ECT outweigh the risk of memory impairment. The
comment also indicates that FDA presents no evidence verifying that the
special controls are effective at mitigating risk or that the special
controls will ensure patients understand the benefits-risks of ECT.
    (Response 16) FDA identified sufficient scientific information to
establish special controls, including adequate instructions for use and
appropriate precautionary language. The special controls along with
general controls provide a reasonable assurance that ECT can be used
safely and effectively for the indications being reclassified to class
II. Regarding the use of the word, believe, by FDA in the proposed
order, FDA's use is of the word believe is a term of art to indicate
its current understanding of an issue in administrative orders. The
term, believe, is also used in both the FD&C Act and FDA's regulations.
    The risk of memory impairment following ECT treatment is addressed
in the special controls. The risk of cognitive and memory impairment
can be mitigated by establishing the technical parameters for the
device along with non-clinical testing data to confirm the electrical
characteristics of the output waveform. The existing clinical
performance data for ECT in treating catatonia or a severe MDE
associated with MDD or BPD provides evidence that the cognitive
impairment and related effects are transient (Refs. 5 and 34) and
supports a reasonable assurance of SE. This risk is further mitigated
by providing information to both the user and patient, in the form of
labeling, on the potential adverse effects of the device, alternative
treatments, and a prominent warning that ECT device use may be
associated with: disorientation, confusion, and memory problems and is
limited in its long-term effectiveness (greater than 3 months). These
risks can also be mitigated by providing instructions to the user that
include recommendations on cognitive status monitoring prior to
beginning ECT and during the course of treatment. Providing this
information helps patients and healthcare professionals to make
informed choices about how and when to use ECT to maximize benefits and
minimize potential adverse effects.

D. Comments on Regulatory Process of the Proposed Order

    In this section, comments on process concerns of the order are
categorically grouped together so that the responses could be addressed
by topic instead of

each comment considered independently.
    (Comment 17) Several comments provided recommendations on
additional sources of information that FDA should consider in regards
to reclassification of ECT. Comments suggested that FDA should review
State ECT registries for information on use and outcomes. Comments
suggested FDA should require new clinical trials, additional postmarket
surveillance, and/or establish patient registries for the purposes of:
(1) Establishing long-term risks, such as the potential for shortened
life; (2) monitoring and assessing memory and cognitive functioning
over a period of a year or more to determine if memory loss is
permanent; and (3) determining if patients experienced any long-term
benefit. A comment indicates that MDR data should be used in the
classification determination for ECT. The comment attaches an analysis
of the FDA MDR database search showing that most patients report
lasting memory and cognition impairment, and other side effects that
affect work, education, and social relationships. The comment indicates
that FDA's MDR database shows systematic discrepant reporting of ECT
adverse events (e.g., description of burns coded with event type,
malfunction). Comments requested that FDA hold another public meeting
about the classification of ECT that includes testimony from ECT
patients because of the ``new information'' provided in the public
comments.
    (Response 17) FDA agrees that State or national registries may play
a role in medical device surveillance to provide additional detailed
information about patients, procedures, and devices not routinely
collected by electronic health records and administrative or claims
data. The State of Texas has for several years maintained a registry of
all ECT treatments in the State in a given year. Data on these
treatments are provided in an annual report to the governor (see
https://www.dshs.texas.gov/mhsa/bhmd/ect/, Ref. 55). The most recent
report provides data for fiscal year 2016. This report summarizes
17,006 treatments given to 2,675 patients. Severe complications
included 0 fractures, 0 episodes of apnea, 0 cases of cardiac arrest
without death, and 1 death within 14 days of treatment that was
reported to be the result of a drug overdose. This report concludes
that, overall, patients experienced less severe symptomology after ECT
treatment, which demonstrates the overall effectiveness of treatment.
These data are consistent with the published literature and do not
provide ``new information'' that would change the recommendation in the
final order.
    FDA requires manufacturers to submit MDRs of adverse events when
their device may have caused or contributed to a death, serious injury,
or in certain situations when their device has malfunctioned. FDA
acknowledges that there are limitations to the use of MDR reports for
determining the cause and frequency of adverse events. Confirming
whether a device caused a specific event can be difficult based solely
on information provided in a given MDR report. Establishing a cause-
and-effect relationship is especially difficult if circumstances
surrounding the event have not been verified or if the device in
question has not been directly evaluated. FDA does not typically have
complete information on the number of times devices of a certain type
are used from which to calculate adverse event rates. MDR data does not
represent all known safety information for a medical device and should
be interpreted in the context of other available information when
making device-related or treatment decisions. Healthcare professionals,
patients, caregivers, and consumers are encouraged to submit voluntary
reports detailing treatment parameters and outcomes to MedWatch: The
FDA Safety Information and Adverse Event Reporting Program, for serious
adverse events that may be associated with a medical device, as well as
use errors, product quality issues, and therapeutic failures (Ref. 56).
Reports of adverse events are monitored by FDA for safety signals that
may warrant changes to device regulation.
    Despite the limitations of MDR data described above, as part of its
review of the comments submitted to the ECT public dockets, FDA
conducted an updated review of the MDR database covering the period
from February 2011 through December 2017. This review identified an
additional 27 reports, all of which are voluntary reports. No reports
for individuals less than 18 years of age were reported to the MDR
database. Similar to the reports included in the Executive Summary for
the classification panel, the most commonly cited adverse event type
was cognitive changes, notably memory loss (52 percent). Other commonly
reported adverse events included general emotional/psychiatric (e.g.,
anxiety, emotional changes), general motor (e.g., shaking/tremors), and
four reports of either tissue damage (not specified) or burns. Thus,
FDA concluded that no new types of adverse events have been identified
that would warrant changes to the proposed reclassification order.
    (Comment 18) Several comments raised concern with how the ECT 2011
classification panel was conducted. Several comments indicated that the
proposed reclassification was not supported by the panel, because the
classification panel did not reach consensus regarding whether any of
the indications should be class II. Comments said that FDA
misrepresented the classification panel results regarding consensus on
classification of ECT. Another comment alleges that FDA improperly
influenced the makeup and deliberations of the classification panel.
    (Response 18) FDA considers the deliberations as well as the
recommendations by the classification panel meeting in determining the
appropriate classification of a device under section 513(a) of the FD&C
Act. The classification panel discussions and recommendations are
considered as part of FDA's decision whether to revise classification
of a device (see section 515(i)(2) of the FD&C Act). Although the panel
provides recommendations with respect to the classification of devices,
FDA is also not required to follow the classification panel
recommendations. Regarding ECT, the panel did not reach a consensus on
its classification for any of the proposed conditions for
reclassification. There were a variety of opinions and judgments
provided both in support of and in opposition to reclassification. The
opinions expressed by the classification panel were carefully reviewed
and considered along with other information including professional
organization practice guidelines, MDR reports, and published scientific
studies.
    Based on this evidence from multiple sources, FDA has determined
that special controls, in combination with general controls, establish
a reasonable assurance of SE by mitigating the risks associated with
ECT for the uses being reclassified (as discussed in section X, 80 FR
81223 at 81230, December 29, 2015). In accordance with section
515(i)(2) of the FD&C Act, based on valid scientific evidence 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 also now revising the
classification of ECT for treatment of catatonia or a severe MDE
associated with MDD or BPD who are treatment-resistant or who require a
rapid response due to the severity of their psychiatric or medical
condition in patients ages 13 years and older, from class III to class
II (special controls) (see subsections A and B of this section).

    FDA disagrees with the comment that FDA improperly influenced the
2011 classification panel. On January 27-28, 2011, FDA held a meeting
of the Neurological Devices Classification Panel to discuss the
classification of ECT devices for treatment of several disorders. FDA
has standard procedures in place for establishing a classification
panel meeting consistent with the requirements of the Federal Advisory
Committee Act, other relevant statutes (e.g., the FD&C Act),
regulations (e.g., 21 CFR 14.25 and 14.29), and Agency guidance. As
required for all classification panel meetings, FDA conducted the
proper screening and vetting of classification panel members for the
2011 Panel meeting. FDA ensured the classification panel included
representatives with expertise in several relevant mental health
disciplines. The ECT classification panel meeting meets the requirement
under section 513(b)(1) of the FD&C Act for a device classification
panel meeting.
    The conduct of the 2011 Panel meeting is described in the
transcript of the meeting and the 24 Hour Summary (Ref. 57). FDA
presented the general regulatory background, brief clinical history of
ECT use, and ECT-specific regulatory history. This was followed by an
open public hearing. Then, FDA presented the FDA's safety analysis,
which included a review of responses to a public docket on ECT
reclassification, manufacturer docket responses, and an adverse event
database review. In addition, FDA presented a focused review of
specific adverse events, including cognitive and memory adverse events,
neuropathological changes, and death. Following the safety review, FDA
presented a review of the effectiveness of ECT. The classification
panel then proceeded to their deliberations regarding the questions
posed by FDA. The classification panel agreed that the list of risks
provided by FDA were appropriate for inclusion with some minor
modifications and deletions. The classification panel recommended
physician labeling for pre-ECT assessment, including pertinent history,
physical examination, other clinically relevant studies, appropriate
procedure monitoring and administration, and appropriate clinical
management. When presented with potential regulatory controls that FDA
could apply to ECT to mitigate risks of adverse cognitive and memory
effects, especially with respect to anterograde and retrograde memory
functioning, the classification panel agreed that cognitive function
should be monitored prior to ECT and throughout the course of
treatment. The classification panel agreed that the existing clinical
data do not provide evidence that ECT treatment is associated with
neuropathological changes. Finally, the classification panel provided
overall recommendations for the class II or III classification of ECT
devices for specific indications for use, including depression
(unipolar and bipolar), schizophrenia, bipolar manic (and mixed)
states, schizoaffective disorder and schizophreniform disorder, and
catatonia. There was classification panel consensus recommending class
III for schizophrenia, bipolar manic states, and schizoaffective and
schizophreniform disorder. The classification panel did not reach
consensus on the classification of ECT for depression (unipolar and
bipolar) and catatonia.
    (Comment 19) Several comments related to the information used to
support reclassification. Several comments indicated that the
scientific evidence, medical studies, meta-analyses and literature
reviews cited in the proposed order do not constitute new evidence or
reinterpret previously published evidence and are insufficient to
justify the reclassification. Comments say FDA ignored the 2010 meta-
analysis from Read and Bentall that found, after reviewing hundreds of
studies, no evidence that ECT treatment had any benefit for any
population lasting beyond a few days and did not prevent suicide.
    (Response 19) In accordance with section 515(i)(2) of the FD&C Act,
FDA is reclassifying the ECT device from class III to II (special
controls) for use in treating catatonia or a severe MDE associated with
MDD or BPD in patients age 13 years and older who are treatment-
resistant or who require a rapid response due to the severity of their
psychiatric or medical condition. FDA has made this reclassification
decision based on FDA's evaluation of the following sources of
information: (1) Published literature referenced in the Executive
Summary to the 2011 Panel; (2) comments and literature received in the
ECT public dockets, as discussed above; (3) clinical practice
guidelines; (4) review of MDRs in the FDA MAUDE database); and (5) the
additional post-2011 scientific information that was provided to FDA in
comments to the 2015 proposed order. Based on FDA's evaluation of the
totality of the evidence under the criteria set forth in section 513(a)
of the FD&C Act, FDA believes that there is valid scientific evidence
to support FDA's decision to reclassify the ECT device from class III
to II (special controls) for the intended uses described previously.
    FDA disagrees with the conclusions of the 2010 Read and Bentall
analysis. Specifically, FDA conducted an independent review and several
publications, as well as reviews of the published literature, support
the use of ECT in treating catatonia or a severe MDE associated with
MDD or BPD in patients age 13 years and older who are treatment-
resistant or who require a rapid response due to the severity of their
psychiatric or medical condition (Ref. 33, 34 and 58-60). Observations
from these individual studies, retrospective reviews, and meta-analyses
consistently reported favorable SE clinical outcomes for the
indications being reclassified by this final order. In addition, as
part of the preparations for the 2011 Classification Panel Meeting, FDA
conducted a systematic review of the scientific literature regarding
the SE of ECT for a variety of psychiatric conditions. FDA conducted a
meta-analysis of the data provided in all studies that met criteria for
inclusion in this systematic review. Based upon this review and meta-
analysis, and the totality of evidence, FDA determined that there was
reasonable assurance of the SE of ECT for the class II indications in
this final order.
    (Comment 20) Several concerns were raised about the process for the
proposed order. Comments indicated the guidance should not be used or
issued prior to finalization of the final order. Comments indicated
there was inadequate time to comment on the proposed order due to
timing of the comment period coinciding with holidays at the end of the
year, and weekends being included in the 90-day response time. Comments
indicated that two dockets (one for the proposed order and one for the
draft guidance) on ECT made commenting more difficult. Commenters
objected to elimination of mass mail in campaigns and duplicative or
near-duplicative letters.
    (Response 20) FDA agrees with the comment that guidance should not
be used or issued prior to finalization of the final order. Final
guidance will not be issued prior to issuance of the final order. FDA
believes the correct process was followed for the proposed order issued
for ECT. FDA determined it was beneficial to publish the proposed order
and draft guidance on ECT concurrently to ensure that all relevant
information pertinent to the potential reclassification of ECT, along
with a recommended strategy for demonstrating substantial equivalence
for ECT devices subject to 510(k), was available to the public at the
same time.

FDA believes that a 90-day comment period was ample time to allow the
public to comment on the proposed order and concurrently released draft
guidance and is consistent with the timeframes for other classification
and reclassification efforts. Commenting on two dockets related to ECT
rather than one docket does require additional effort by commenters.
However, FDA had taken two different actions related to ECT (proposing
a reclassification and issuing draft guidance), such that two dockets
were made available to provide the option of commenting on one or both
of these proposed actions. Documents that are in ``draft'' form are not
implemented by FDA unless and until finalized.
    Information submitted as part of a mass campaign was also reviewed.
However, while the content of these letters is considered and responded
to, FDA does not individually respond to the same information contained
in mass campaign letters and duplicative letters. This allows FDA to
efficiently utilize resources when reviewing comments. As noted
previously, although over 3,400 comments were received, comments were
categorically grouped together so that responses are addressed by topic
instead of responding independently to each individual comment.
    (Comment 21) Several comments argue that the terms ``treatment
resistant'' and ``require rapid response'' are vague, particularly to
non-clinicians. Several comments asked for clarification on the number
and types of treatments, as well as the duration of treatment that
should be tried prior to being labeled treatment-resistant. Several
comments indicated that there was not consensus from the literature and
professional organizations on the meaning of treatment-resistant. A
comment indicates that defining treatment-resistant depression as the
failure of two antidepressants is not appropriate because
antidepressants are not effective for every patient and there are other
treatments that may be effective that should be used prior to ECT.
Several comments indicated that psychotherapy or other non-medical
treatments should be tried prior to ECT. Several comments were
concerned that the lack of clarity of these terms would lead to misuse
of ECT. Several other comments indicated that the terms ``treatment-
resistant'' and ``require rapid response'' were well understood and
described in applicable medical literature and the Diagnostic and
Statistical Manual of Mental Disorders (Ref. 61).
    (Response 21) FDA identifies the intended population in which ECT
is classified in class II as patients who are treatment-resistant
because ECT is not a currently established first-line treatment, except
when rapid response is needed due to the severity of the patient's
psychiatric or medical condition. FDA acknowledges that these terms may
not be entirely clear to patients. However, comments by healthcare
professionals generally indicated that the terms are well understood by
the staff who would be prescribing or using this therapy. The need for
rapid response and the criteria for treatment-resistant can be based on
clinical judgment. The information on the intended patient population
that, as part of the special controls, must be listed on the device
label (Sec.  882.5940(b)(1)(viii)(D)) is directed toward the
practitioner licensed by law to administer or use the device.
    (Comment 22) A comment asks FDA to delete the recommendation in
Sec.  882.5940(b)(1)(viii)(B)(7) for ``formal neuropsychological
assessment'' from the labeling because it is not the norm and would
create barriers to the availability and timeliness of care in that such
assessments are costly and difficult to access.
    (Response 22) FDA recognizes that not all ECT practitioners have
access to neuropsychologists who conduct formal neuropsychological
assessment. However, FDA believes that the known risk of cognitive
adverse events can be mitigated by the special controls that require
user instructions recommending cognitive status monitoring prior to
beginning ECT and throughout the course of treatment via a formal
neuropsychological assessment. If cognitive abilities decline during
the course of treatment, steps can be taken to avoid further decline.
    (Comment 23) A comment stated depression is sometimes associated
with cognitive problems and urges FDA to require that all providers of
ECT assess patients' cognitive and memory functioning when they first
become patients before ECT begins, soon after ECT ends, and at longer
term followup after ECT treatment.
    (Response 23) FDA includes a special control (Sec.
882.5940(b)(1)(viii)(B)(7)) that requires user instructions that
recommend cognitive status monitoring prior to beginning ECT and during
the course of treatment via formal neuropsychological assessment for
evaluating specific cognitive functions (e.g., orientation, attention,
memory, and executive function). FDA acknowledges that autobiographical
memory loss following ECT treatment can occur, so this adverse event
has been included in the labeling for ECT. FDA also acknowledges that
the ``long-term safety and effectiveness of ECT treatment has not been
demonstrated,'' and therefore has included this risk as a warning in
the ECT device labeling that long-term followup may be needed.

E. Comments on Labeling Concerns

    In this section, comments on labeling concerns in using ECT are
categorically grouped together so that the responses could be addressed
by topic instead of each comment considered independently.
    (Comment 24) A comment requested that FDA delete the proposed
warning in Sec.  882.5940(b)(1)(viii)(J) and (ix)(G) (``When used as
intended this device provides short-term relief of symptoms. The long-
term safety and effectiveness of ECT treatment has not been
demonstrated.'') because it is understood that cessation of active
treatment will be associated with cessation of treatment benefits.
    (Response 24) Based upon all available evidence and FDA's own
analysis of the published scientific literature, FDA concluded that the
long-term SE of ECT has not been demonstrated. However, FDA recognizes
that ECT healthcare professionals often conduct longer term treatment
strategies with ECT. The reclassification of ECT does not specifically
address the issue of maintenance or continual ECT, which would be at
the discretion of the healthcare professional. However, as described in
the special controls, results from longer term performance data should
be considered for inclusion in the healthcare professional and patient
labeling, if warranted.
    (Comment 25) A comment asks FDA to replace the word
``contraindications'' in proposed Sec.  882.5940(b)(1)(ix)(A) with the
phrase ``conditions associated with substantially increased risk''
because describing these conditions as contraindications is likely to
restrict access to needed ECT in very rare but life-threatening
situations.
    (Response 25) The use of the word ``contraindications'' here refers
specifically to medical conditions other than psychiatric disorders in
which the use of ECT has been demonstrated to result in serious adverse
events, some of which might be life-threatening. These include unstable
cardiac and pulmonary conditions (e.g., recent heart attack, asthma,
pneumonia) and history of neurological conditions (e.g., stroke,
tumors, increased pressure in the brain). Contraindications are defined
as situations in which the device should not be used because the risk
of use clearly outweighs any benefit. (Ref. 62).

Therefore, FDA believes it is appropriate to keep the language as
initially written in the proposed order.
    (Comment 26) A comment disagrees with definitions of short-term and
long-term memory in Sec.  882.5940(b)(1)(ix)(H)(1). The comment says
equating short-term to anterograde memory loss and long-term to
autobiographical memory loss is unusual in the psychiatric field and
confusing for patients. The comment says short-term could mean: (1)
Lasting for a short period before returning; (2) affecting short-term
memory, i.e., the type of memory where information is held onto for a
few seconds to a few minutes; or (3) anterograde memory, which is the
ability to form new memories. The comment says this labeling does not
clearly describe the range of deficits that patients might experience.
The comment says there is a similar lack of clarity in the use of the
term ``long-term''. The comment says long-term memory typically
includes many different types of information storage, stored for an
extended period of time that could range from more than a few minutes
to years. The comment says many types of cognitive problems can occur
following ECT in addition to anterograde verbal memory and retrograde
autobiographical memory, including retrograde loss of non-personal,
non-rote information (such as knowledge used in daily work tasks), and
impairments in working memory, processing speed, attention, and
executive function. The comment also indicates that there are
discrepancies within the order on the definition of long-term, which is
defined as 1 month in some instance and as 3 months in other instances.
    (Response 26) FDA recognizes that there are a variety of terms used
in the scientific literature with respect to memory function. The
multiple descriptions and definitions of various memory functions such
as ``short-term'' or ``long-term'' memory contributes to significant
confusion both among healthcare professionals and lay persons. FDA will
require the inclusion of the following in the labeling: ``ECT treatment
may be associated with disorientation, confusion and memory loss,
including short-term (anterograde) and long-term (autobiographical)
memory loss following treatment. These side effects tend to go away
within a few days to a few months after the last treatment with ECT.
However, some patients have reported a permanent loss of memories of
personal life events (i.e., autobiographical memory).'' In addition,
because of the complexity of memory loss, cognitive status monitoring
prior to beginning ECT and during the course of treatment via formal
neuropsychological assessment for evaluating specific cognitive
functions (e.g., orientation, attention, memory, executive function) is
included as a special control.
    (Comment 27) A comment asks FDA to change the proposed labeling by
deleting from the list of known risks the phrase, ``a worsening of the
psychiatric symptoms they are being treated for,'' in Sec.
882.5940(b)(1)(ix)(H)(2). The comment notes symptoms may worsen if ECT
is not effective but argues that this is not the same as saying that
symptoms worsen as a known risk of ECT. The comment notes that the
possibility of precipitating a manic episode with ECT treatment is
documented in the scientific literature but is already included in the
listing of potential risks.
    (Response 27) FDA recognizes that worsening of an underlying
medical condition can occur either by: (1) An ineffective treatment or
(2) the treatment itself, particularly when it exacerbates the
symptoms. Without additional scientific evidence to distinguish between
these two causes for the use of ECT, this language is included as a
potential risk.
    (Comment 28) Several comments indicated that labeling was not a
sufficient mitigation for the risks associated with ECT. Several
comments indicated that labeling was not a sufficient mitigation
because the label might not be read, understood, or followed.
    (Response 28) FDA notes that regardless of the classification and
the risk presented by medical devices, they have the potential to cause
harm to patients if the labeling is not read, understood, or followed.
FDA has purposefully included, per the special controls, specific
mitigations in the required labeling to ensure patient protections and
transparency related to the benefit-risk profile of ECT. Labeling
directed to healthcare professionals and patients further help to
mitigate the risks of ECT because it must include instructions for use
and a description of the known risks.
    (Comment 29) A comment asks FDA to delete in Sec.
882.5940(b)(1)(ix)(H)(3)(v) the phrase ``insufficient, or lack of
breathing'' as a pulmonary complication and add a new item ``prolonged
action of anesthetic agents associated with insufficient or lack of
breathing.'' The comment says the proposed text implies that
insufficient or lack of breathing may be a long-term complication of
ECT, whereas apnea is an expected effect of neuromuscular blocking
agents. The comment notes insufficient or lack of breathing may be
prolonged in some individuals but can be addressed through continued
ventilation and oxygenation by an anesthesia provider.
    (Response 29) FDA agrees that the warnings related to pulmonary
risks were unclear and has revised Sec.  882.5940(b)(1)(ix)(H)(3)(v) to
identify these pulmonary risks associated with the use of general
anesthesia and neuromuscular blocking agents.

F. Comments Outside of the Scope of This Final Order

    There were several comments submitted that were outside the scope
of this Final Order and in this section we explain why. Also, in this
section comments are categorically grouped together so that the
responses are by topic.
    (Comment 30) A number of comments recommended that FDA take action
to not allow the American Psychiatric Association (APA) to use the
phrase ``safe, effective treatment'' and to prevent the APA and the
National Institute for Mental Health from explicitly using some of the
claims on ECT treatment.
    (Response 30) FDA generally does not have the authority to direct
medical associations and other government agencies on how to phrase
their scientific evaluation of medical devices. Therefore, the requests
are outside the scope of this final order.
    (Comment 31) Several comments raised concerns regarding insurance
coverage with different indications in different regulatory classes.
Several comments indicated that coverage issues may reduce patient
options for treatment.
    (Response 31) FDA has no authority over commercial health insurance
carriers. Under section 513(e) 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 ECT treatment.