
[Federal Register Volume 76, Number 152 (Monday, August 8, 2011)]
[Proposed Rules]
[Pages 48062-48070]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-19957]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 882

[Docket No. FDA-2011-N-0504]


Effective Date of Requirement for Premarket Approval for Cranial 
Electrotherapy Stimulator

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require 
the filing of a premarket approval application (PMA) or a notice of 
completion of a product development protocol (PDP) for the Cranial 
Electrotherapy Stimulator. The Agency is also summarizing its proposed 
findings regarding the degree of risk of illness or injury designed to 
be eliminated or reduced by requiring this device to meet the statute's 
approval requirements and the benefits to the public from the use of 
the device. In addition, FDA is announcing the opportunity for 
interested persons to request that the Agency change the classification 
of the cranial electrotherapy stimulator based on new information. This 
action implements certain statutory requirements.

DATES: Submit either electronic or written comments by November 7, 
2011. Submit requests for a change in classification by August 23, 
2011. FDA intends that, if a final rule based on this proposed rule is 
issued, anyone who wishes to continue to market the device will need to 
submit a PMA within 90 days of the effective date of the final rule. 
Please see section XII of this document for the effective date of any 
final rule that may publish based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2011-
N-0504 by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Fax: 301-827-6870.
     Mail/Hand delivery/Courier (For paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2011-N-0504 for this rulemaking. All comments 
received may be posted without change to http://www.regulations.gov, 
including any personal information provided. For additional information 
on submitting comments, see the ``Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

[[Page 48063]]


FOR FURTHER INFORMATION CONTACT: Timothy Marjenin, Center for Devices 
and Radiological Health, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 66, rm. 2258, Silver Spring, MD 20993-0002, 301-
796-6502, e-mail: timothy.marjenin@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended 
by the Medical Device Amendments of 1976 (the 1976 amendments) (Pub. L. 
94-295), the Safe Medical Devices Act of 1990 (SMDA) (Pub. L. 101-629), 
and the Food and Drug Administration Modernization Act of 1997 (FDAMA) 
(Pub. L. 105-115), the Medical Device User Fee and Modernization Act of 
2002 (MDUFMA) (Pub. L. 107-250), the Medical Devices Technical 
Corrections Act (Pub. L. 108-214), and the Food and Drug Administration 
Amendments Act of 2007 (Pub. L. 110-85), among other amendments, 
establish a comprehensive system for the regulation of medical devices 
intended for human use. Section 513 of the FD&C Act (21 U.S.C. 360c) 
established three categories (classes) of devices, reflecting the 
regulatory controls needed to provide reasonable assurance of their 
safety and effectiveness. The three categories of devices are class I 
(general controls), class II (special controls), and class III 
(premarket approval).
    Under section 513 of the FD&C Act, devices that were in commercial 
distribution before the enactment of the 1976 amendments, May 28, 1976 
(generally referred to as preamendments devices), are classified after 
FDA has: (1) Received a recommendation from a device classification 
panel (an FDA advisory committee); (2) published the panel's 
recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976 (generally referred to as postamendments devices) are 
automatically classified by section 513(f) of the FD&C Act into class 
III without any FDA rulemaking process. Those devices remain in class 
III and require premarket approval unless, and until, the device is 
reclassified into class I or II or FDA issues an order finding the 
device to be substantially equivalent, in accordance with section 
513(i) of the FD&C Act, to a predicate device that does not require 
premarket approval. The Agency determines whether new devices are 
substantially equivalent to predicate devices by means of premarket 
notification procedures in section 510(k) of the FD&C Act (21 U.S.C. 
360(k)) and 21 CFR part 807.
    A preamendments device that has been classified into class III may 
be marketed by means of premarket notification procedures (510(k) 
process) without submission of a PMA) until FDA issues a final 
regulation under section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) 
requiring premarket approval. Section 515(b)(1) of the FD&C Act 
establishes the requirement that a preamendments device that FDA has 
classified into class III is subject to premarket approval. A 
preamendments class III device may be commercially distributed without 
an approved PMA or a notice of completion of a PDP until 90 days after 
FDA issues a final rule 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. Also, a preamendments device subject 
to the rulemaking procedure 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 rule 
requiring the submission of a PMA for the device. At that time, an IDE 
is required only if a PMA has not been submitted or a PDP completed.
    Section 515(b)(2)(A) of the FD&C Act provides that a proceeding to 
issue a final rule to require premarket approval shall be initiated by 
publication of a notice of proposed rulemaking containing: (1) The 
regulation; (2) proposed findings with respect to the degree of risk of 
illness or injury designed to be eliminated or reduced by requiring the 
device to have an approved PMA or a declared completed PDP and the 
benefit to the public from the use of the device; (3) an opportunity 
for the submission of comments on the proposed rule and the proposed 
findings; and (4) an opportunity to request a change in the 
classification of the device based on new information relevant to the 
classification of the device.
    Section 515(b)(2)(B) of the FD&C Act provides that if FDA receives 
a request for a change in the classification of the device within 15 
days of the publication of the notice, FDA shall, within 60 days of the 
publication of the notice, consult with the appropriate FDA advisory 
committee and publish a notice denying the request for change in 
reclassification or announcing its intent to initiate a proceeding to 
reclassify the device under section 513(e) of the FD&C Act. Section 
515(b)(3) of the FD&C Act provides that FDA shall, after the close of 
the comment period on the proposed rule and consideration of any 
comments received, issue a final rule to require premarket approval or 
publish a document terminating the proceeding together with the reasons 
for such termination. If FDA terminates the proceeding, FDA is required 
to initiate reclassification of the device under section 513(e) of the 
FD&C Act, unless the reason for termination is that the device is a 
banned device under section 516 of the FD&C Act (21 U.S.C. 360f).
    When a proposed rule to require premarket approval for a 
preamendments device is finalized, section 501(f)(2)(B) of the FD&C Act 
(21 U.S.C. 351(f)(2)(B)) requires that a PMA or notice of completion of 
a PDP for any such device be filed within 90 days of the date of 
issuance of the final rule or 30 months after the final classification 
of the device under section 513 of the FD&C Act, whichever is later. If 
a PMA or notice of completion of a PDP is not filed by the later of the 
two dates, commercial distribution of the device is required to cease 
since the device would be deemed adulterated under section 501(f) of 
the FD&C Act.
    The device may, however, be distributed for investigational use if 
the manufacturer, importer, or other sponsor of the device complies 
with the IDE regulations. If a PMA or notice of completion of a PDP is 
not filed by the later of the two dates, and the device does not comply 
with IDE regulations, 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. Shipment of devices in interstate commerce 
will be subject to injunction under section 302 of the FD&C Act (21 
U.S.C. 332), and the individuals responsible for such shipment will be 
subject to prosecution under section 303 of the FD&C Act (21 U.S.C. 
333). In the past, FDA has requested that manufacturers take action to 
prevent the further use of devices for which no PMA or PDP has been 
filed and may determine that such a request is appropriate for the 
cranial electrotherapy stimulator.
    The FD&C Act does not permit an extension of the 90-day period 
after issuance of a final rule within which an application or a notice 
is required to be filed. The House Report on the 1976 amendments states 
that: ``[t]he thirty month grace period afforded after

[[Page 48064]]

classification of a device into class III * * * is sufficient time for 
manufacturers and importers to develop the data and conduct the 
investigations necessary to support an application for premarket 
approval (H. Rept. 94-853, 94th Cong., 2d sess. 42 (1976)).''
    The SMDA added section 515(i) to the FD&C Act requiring FDA to 
review the classification of preamendments class III devices for which 
no final rule requiring the submission of PMAs has been issued, and to 
determine whether or not each device should be reclassified into class 
I or class II or remain in class III. For devices remaining in class 
III, the SMDA directed FDA to develop a schedule for issuing 
regulations to require premarket approval. The SMDA does not, however, 
prevent FDA from proceeding immediately to rulemaking under section 
515(b) of the FD&C Act on specific devices, in the interest of public 
health, independent of the procedures of section 515(i). Proceeding 
directly to rulemaking under section 515(b) of the FD&C Act is 
consistent with Congress' objective in enacting section 515(i), i.e., 
that preamendments class III devices for which PMAs have not been 
previously required either be reclassified to class I or class II or be 
subject to the requirements of premarket approval. Moreover, in this 
proposal, interested persons are being offered the opportunity to 
request reclassification of the cranial electrotherapy stimulator.

II. Dates New Requirements Apply

    In accordance with section 515(b) of the FD&C Act, FDA is proposing 
to require that a PMA or a notice of completion of a PDP be filed with 
the Agency for the cranial electrotherapy stimulator within 90 days 
after issuance of any final rule based on this proposal. An applicant 
whose device was legally in commercial distribution before May 28, 
1976, or whose device has been found to be substantially equivalent to 
such a device, will be permitted to continue marketing such class III 
devices during FDA's review of the PMA or notice of completion of the 
PDP. FDA intends to review any PMA for the device within 180 days, and 
any notice of completion of a PDP for the device within 90 days of the 
date of filing. FDA cautions that under section 515(d)(1)(B)(i) of the 
FD&C Act, the Agency may not enter into an agreement to extend the 
review period for a PMA beyond 180 days unless the Agency finds that 
``the continued availability of the device is necessary for the public 
health.''
    FDA intends that under Sec.  812.2(d), the preamble to any final 
rule based on this proposal will state that, as of the date on which 
the filing of a PMA or a notice of completion of a PDP is required to 
be filed, the exemptions from the requirements of the IDE regulations 
for preamendments class III devices in Sec.  812.2(c)(1) and (c)(2) 
will cease to apply to any device that is: (1) Not legally on the 
market on or before that date or (2) legally on the market on or before 
that date but for which a PMA or notice of completion of a PDP is not 
filed by that date, or for which PMA approval has been denied or 
withdrawn.
    If a PMA or notice of completion of a PDP for the cranial 
electrotherapy stimulator is not filed with FDA within 90 days after 
the date of issuance of any final rule requiring premarket approval for 
the device, commercial distribution of the device must cease. The 
device may be distributed for investigational use only if the 
requirements of the IDE regulations are met. The requirements for 
significant risk devices include submitting an IDE application to FDA 
for its review and approval. An approved IDE is required to be in 
effect before an investigation of the device may be initiated or 
continued under Sec.  812.30. FDA, therefore, cautions that IDE 
applications should be submitted to FDA at least 30 days before the end 
of the 90-day period after the issuance of the final rule to avoid 
interrupting investigations.

III. Proposed Findings With Respect to Risks and Benefits

    As required by section 515(b) of the FD&C Act, FDA is publishing 
its proposed findings regarding: (1) The degree of risk of illness or 
injury designed to be eliminated or reduced by requiring that the 
cranial electrotherapy stimulator have an approved PMA or a declared 
completed PDP and (2) the benefits to the public from the use of the 
cranial electrotherapy stimulator.
    These findings are based on the reports and recommendations of the 
advisory committee (panel) for the classification of this device along 
with information submitted in response to the 515(i) Order, (74 FR 
16214, April 9, 2009), and any additional information that FDA has 
encountered. Additional information regarding the risks as well as 
classification associated with this device type can be found in the 
following documents published in the Federal Register on these dates: 
November 28, 1974 (43 FR 55716), September 4, 1979 (44 FR 51770), 
January 6, 1989 (54 FR 550), August 31, 1993 (58 FR 45865), August 24, 
1995 (60 FR 43967), November 22, 1996 (61 FR 59448), January 28, 1997 
(62 FR 4023), and June 4, 1997 (62 FR 30456 and 62 FR 30600).

IV. Devices Subject to This Proposal

    Cranial electrotherapy stimulator (21 CFR 882.5800)

A. Identification

    A cranial electrotheraphy stimulator is a device that applies 
electrical current to a patient's head to treat insomnia, depression, 
or anxiety.

B. Summary of Data

    The Neurological Devices Panel that discussed original 
classification for the cranial electrotherapy stimulator (CES) device 
in 1977 and 1978 ultimately recommended that the device be classified 
into class III because satisfactory device effectiveness had not been 
demonstrated. The panel considered information from the National 
Research Council, which reviewed 88 published studies on CES and 
concluded that the device has not been shown to be effective in 
treating any of the conditions for which it was prescribed. In 
addition, the panel indicated that it was not possible to establish an 
adequate performance standard for CES because the characteristics of 
the electrical current necessary for potential effectiveness were not 
known. The panel believed that general controls would not provide 
sufficient control over these characteristics, and that the device 
presented a potential unreasonable risk of illness or injury to the 
patient if the practitioner relied on the device, and it was 
ineffective in treating the patient's illness. Therefore, the panel 
recommended that premarket approval was necessary to assure the safety 
and effectiveness of CES devices.
    In support of a subsequent proposed rule in 1993 for classification 
of CES into class III, FDA performed a literature review and identified 
additional studies that had been performed for CES. After a review of 
the scientific literature, FDA concluded that the effectiveness of CES 
had still not been established by adequate scientific evidence.
    FDA has performed a literature search for studies of CES published 
after the 1993 proposed rule (January 1, 1993, to present). Many 
studies were excluded from further review because they were conducted 
on very specific populations (e.g., alcoholics or other types of 
substance abuse), and therefore were not representative of the general 
population suffering from insomnia, anxiety, or depression. Six studies 
were identified for further review (Refs. 1 through 6). FDA also 
identified two relevant meta-analyses (Refs. 7 and 8).
    The Bystritsky et al. study (Ref. 1) was conducted open-label, and 
on only 12

[[Page 48065]]

subjects. The study involved observational baseline versus post-
treatment without a control and therefore provided insufficient 
evidence of safety and effectiveness. The Heffernan study (Ref. 2) 
concludes that a single CES treatment may have physiologic effects; 
however, no outcomes of anxiety, depression or insomnia were measured 
and the study was conducted on only 20 subjects. The Overcash study 
(Ref. 3) was a retrospective study design and used an anxiety rating 
scale that was not validated. The Voris study (Ref. 4) analyzed only a 
subgroup of ``psychiatric subjects'' which included many types of 
anxiety disorders as well as non-anxiety psychiatric disorders. The 
subgroup represents a diagnostically heterogeneous group. The subgroup 
analysis was not pre-specified and the number of subjects per subgroup 
was not specified. The Hyun study (Ref. 5) was a randomized controlled 
trial of 60 subjects. However, the indication under investigation was 
preoperative anxiety, which may not be indicative of an Axis I anxiety 
disorder. Moreover, the outcome measure, a 5-point Likert scale rating 
of anxiety, was not a standardized validated rating instrument. The 
Winick study (Ref. 6), which was a randomized controlled trial of 33 
subjects with anxiety prior to dental procedures and utilized a 7-point 
Likert scale, suffers from the same limitations as the Hyun study.
    The O'Conner meta-analysis (Ref. 7) examined the effect of CES on 
reduction of primary and secondary withdrawal symptoms among various 
chemically dependent populations. The results of this analysis do not 
relate to the question of safety and effectiveness since the labeled 
indications for CES currently include insomnia, depression, or anxiety, 
and not withdrawal symptoms of chemical dependence. The Klawansky meta-
analysis (Ref. 8) was based on an examination of literature on CES 
versus sham treatment. Although the analysis showed CES to be more 
effective than sham for anxiety, the study populations showed great 
heterogeneity of diagnostic categories (e.g., in many cases anxiety was 
not the primary diagnosis, but rather one of a number of symptomatic 
outcome measures collected during a trial). Therefore, it is unclear 
whether the finding can be generalized to support the effectiveness of 
CES in homogeneous populations of individuals suffering from anxiety, 
depression, or insomnia. Also, many of the studies evaluated in the 
Klawansky meta-analysis involved insufficient blinding.
    FDA has concluded from a review of the scientific literature and 
the information provided in the 515(i) call for information (74 FR 
16214) that the effectiveness of CES has not been established by 
adequate scientific evidence and the Agency continues to agree with the 
panel's recommendation.

C. Risks to Health

     Worsening of the condition being treated--If the device is 
not effective and the patient is not treated in a conventional manner, 
the patient's psychological condition may worsen.
     Skin irritation--The electrodes or the conductive cream 
used with the electrodes may cause skin irritation.
     Headaches--Reported cases of adverse effects of CES 
devices include headaches following treatment with electrical 
stimulation.
     Potential risk of seizure--electrical stimulation of the 
brain may result in seizures, particularly in patients with a history 
of seizure.
     Blurred vision--placement of electrodes over the eyes may 
cause blurred vision.
     Potential adverse effects from electrical stimulation of 
the brain--The physiological effects associated with electrical 
stimulation of the brain by these devices have not been studied 
systematically; therefore, adverse effects which may be caused by these 
electrical stimuli remain unknown.

V. PMA Requirements

    A PMA for the cranial electrotherapy simulator must include the 
information required by section 515(c)(1) of the FD&C Act. Such a PMA 
should also include a detailed discussion of the risks identified 
previously, as well as a discussion of the effectiveness of the device 
for which premarket approval is sought. In addition, a PMA must include 
all data and information on: (1) Any risks known, or that should be 
reasonably known, to the applicant that have not been identified in 
this document; (2) the effectiveness of the device that is the subject 
of the application; and (3) full reports of all preclinical and 
clinical information from investigations on the safety and 
effectiveness of the device for which premarket approval is sought.
    A PMA must include valid scientific evidence to demonstrate 
reasonable assurance of the safety and effectiveness of the device for 
its intended use (see Sec.  860.7(c)(2)). Valid scientific evidence is 
``evidence from well-controlled investigations, partially controlled 
studies, studies and objective trials without matched controls, well-
documented case histories conducted by qualified experts, and reports 
of significant human experience with a marketed device, from which it 
can fairly and responsibly be concluded by qualified experts that there 
is reasonable assurance of the safety and effectiveness of a device 
under its conditions of use. * * * Isolated case reports, random 
experience, reports lacking sufficient details to permit scientific 
evaluation, and unsubstantiated opinions are not regarded as valid 
scientific evidence to show safety or effectiveness. * * *'' (21 CFR 
860.7(c)(2)).

VI. PDP Requirements

    A PDP for the cranial electrotherapy stimulator may be submitted in 
lieu of a PMA, and must follow the procedures outlined in section 
515(f) of the FD&C Act. A PDP must provide: (1) A description of the 
device, (2) preclinical trial information (if any), (3) clinical trial 
information (if any), (4) a description of the manufacturing and 
processing of the device, (5) the labeling of the device, and (6) all 
other relevant information about the device. In addition, the PDP must 
include progress reports and records of the trials conducted under the 
protocol on the safety and effectiveness of the device.

VII. Opportunity To Request a Change in Classification

    Before requiring the filing of a PMA or notice of completion of a 
PDP for a device, FDA is required by section 515(b)(2)(A)(i) through 
(b)(2)(A)(iv) of the FD&C Act and Sec.  860.132 to provide an 
opportunity for interested persons to request a change in the 
classification of the device based on new information relevant to the 
classification. Any proceeding to reclassify the device will be under 
the authority of section 513(e) of the FD&C Act.
    A request for a change in the classification of these devices is to 
be in the form of a reclassification petition containing the 
information required by Sec.  860.123, including new information 
relevant to the classification of the device.
    The Agency advises that to ensure timely filing of any such 
petition, any request should be submitted to the Division of Dockets 
Management (see ADDRESSES) and not to the address provided in Sec.  
860.123(b)(1). If a timely request for a change in the classification 
of these devices is submitted, the Agency will, within 60 days after 
receipt of the petition, and after consultation with the appropriate 
FDA resources, publish an order in the Federal Register that either 
denies the

[[Page 48066]]

request or gives notice of its intent to initiate a change in the 
classification of the device in accordance with section 513(e) of the 
FD&C Act and 21 CFR 860.130 of the regulations.

VIII. Environmental Impact

    The Agency has determined under 21 CFR 25.30(h) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

IX. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5 
U.S.C. 601-612) and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all 
costs and benefits of available regulatory alternatives and, when 
regulation is necessary, to select regulatory approaches that maximize 
net benefits (including potential economic, environmental, public 
health and safety, and other advantages; distributive impacts; and 
equity). The Agency believes that this proposed rule is not a 
significant action under Executive Order 12866.
    The Regulatory Flexibility Act requires Agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The Agency proposes to certify that the rule would 
not have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that Agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $136 million, using the most current (2010) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any one-year expenditure that would meet or 
exceed this amount.

A. Benefits of the Proposed Rule

    The proposed requirement for PMAs or PDPs for CES would generate 
social benefits equal to the value of the information generated by the 
safety and effectiveness tests that CES producers would be required to 
conduct under the proposed call for PMAs or PDPs. Provided first to 
FDA, this information would eventually assist physicians, patients and 
insurance providers in making more informed decisions about CES.
    There is reason to believe that current decisions about CES use are 
based on incomplete information. In their 1995 meta-analysis of CES 
research, Klawansky et al. (Ref. 8) find that most CES studies in the 
literature are beset with weaknesses, such as small sample size, 
incomplete statistical reporting, and potential bias from authors who 
have commercial interests in CES products. Klawansky and coauthors also 
express concern that only three of the 18 studies they examined were 
truly double-blinded, and patient blinding may have been insufficient 
in some cases due to the difficulty of mimicking in sham treatment the 
sensation produced by CES. More recent literature indicates that there 
is still much uncertainty about the safety and effectiveness of CES.
    If consumers, up until now, have been overestimating the safety and 
effectiveness of CES devices, then demand for these products would 
decrease as a result of the call for PMAs or PDPs, and consumers would 
purchase fewer CES devices and services than under the previous process 
whereby CES devices were cleared under the 510(k) process. For all the 
units purchased under the 510(k) clearance process that would not be 
purchased under the PMA or PDP approval process, society is currently 
incurring a cost equal to the difference between the producer's cost of 
producing that unit and the dollar value of the health benefit 
experienced by the consumer. The avoidance of this cost represents the 
per-unit benefit to society of the proposed requirement for PMAs or 
PDPs; summing over all currently-marketed units yields society's total 
benefit. This sum is bounded above by current consumer expenditure on 
CES devices (further discussion of this point appears in the Technical 
Appendix in section IX.D of this document).
    Consumer expenditure on CES can be approximated by finding total 
producer revenue (this is only an approximation because any applicable 
taxes drive a wedge between expenditure and revenue). FDA estimates 
that there are approximately 11 producers currently marketing CES 
devices. Six of these producers appear in FDA's Data universal 
numbering system database, with sales revenue for the six ranging from 
$100,000 to $1.2 million per year. Manta.com (Ref. 9) reports sales 
revenue of less than $0.5 million for one of the producers not 
appearing in Data universal numbering system. (It appears that few CES 
producers market non-CES goods or services, so most of the firms' 
revenue can be attributed to CES sales.) The average annual sales 
revenue of the 7 producers for whom we have data is $515,000. Assuming 
that this average equals the CES industry's overall average yields an 
estimate of annual CES producer revenue of 11 x $515,000=$5.67 million. 
As mentioned previously, in the case where additional safety and 
effectiveness information decreases demand, this revenue total provides 
an upper bound on the estimated benefit to society of requiring PMAs or 
PDPs for CES devices.
    If the additional testing associated with class III PMA or PDP were 
to reveal that CES devices are safer and more effective than consumers 
currently believe, then demand for these products would increase. In 
this case, consumers currently purchase too few rather than too many 
CES devices as a result of incomplete information, and the benefit of 
the requirement for PMAs or PDPs would come from the increased use and 
associated health benefits of the devices. As discussed in the 
Technical Appendix in section IX.D of this document, FDA cannot in this 
case estimate a bound on the total social benefit of requiring PMAs or 
PDPs. FDA requests comment on this issue and on all methods and results 
of our benefits estimation.

B. Costs of the Proposed Rule

    Under the proposed rule, FDA would require producers in this 
industry to obtain PMA or establish a PDP before marketing new 
products. Currently, a CES producer receives clearance to market by 
submitting a 510(k). Therefore, the rule-induced cost per new product 
would be the difference between the cost of preparing and submitting a 
PMA application (which we assume to be approximately the same with PDP 
as with traditional PMA) and the cost of preparing and submitting a 
510(k) application. Blozan and Tucker (Ref. 10) estimate the cost of an 
average 510(k) at $500; since the mean number of pages for the 510(k) 
submissions in their sample is 24, the estimated cost per page is $21, 
or $36 after adjusting for inflation (Ref. 11). FDA records indicate 
that, recently, the one or two cranial electrotherapy stimulator 510(k) 
submissions received per year have consisted of several hundred pages 
each. Assuming an average of 300 pages per submission and a cost per 
page of $36 yields an average cost of preparing and submitting a 510(k) 
of $11,000. FDA

[[Page 48067]]

has estimated an upper bound on the cost of PMA at approximately 
$1,000,000 (see, for example, 73 FR 7498 at 7501, February 8, 2008); 
this yields a difference of $989,000 between the costs of PMA and 
510(k) preparation. Multiplying this cost difference by the recent 
average of 1.5 new CES submissions per year yields an annual rule-
induced cost equal to $1.48 million. Additionally, producers of CES 
products that are already on the market would need to submit PMA 
applications, costing approximately $1 million each. FDA believes that 
there are approximately 13 such products, so there would be a rule-
induced upfront cost of $13 million.
    These cost estimates are only correct if no producers would be 
dissuaded from introducing new products or seeking approval for 
currently-marketed products by the cost of submitting a PMA application 
or by changes in the possibility that FDA grants approval. In cases 
where producers are dissuaded from entering or attempting to stay in 
the market, the cost to industry of the proposed rule would be the 
foregone expected profit on the withdrawn or withheld CES devices, 
which is necessarily less than the cost of PMA submission (otherwise, 
the producers in question would not be dissuaded from seeking PMA); the 
$13 million upfront and $1.48 million annual estimates mentioned 
previously thus provide upper bounds on the submission-related cost 
that would be borne by industry. Excluded from these totals is the 
welfare loss that would be borne by consumers who would, in the absence 
of the proposed rule, use the CES devices that would be withdrawn or 
withheld from the market as a result of the call for PMAs or PDPs. Due 
to the lack of sufficient market data, we cannot quantify these 
consumers' welfare loss. FDA requests comment on this issue and on all 
methods and results of our cost estimation.
    In addition to the cost to industry of preparing and submitting 
PMAs or PDPs, the proposed rule would impose review costs on FDA. 
Geiger (Ref. 12) estimated that, for devices reviewed by FDA's Center 
for Devices and Radiological Health in 2003 and 2004, review costs were 
$563,000 per PMA and $13,400 per 510(k). Updated for inflation (with 
Ref. 11) to 2010 dollars, these review costs become $653,000 per PMA 
and $15,500 per 510(k). Thus, the proposed rule's review-related costs 
are expected to equal $8.49 million (= 13 x $653,000) upfront and 
$956,000 (= 1.5 x [$653,000 -$15,500]) per subsequent year. A portion 
of this total will be paid by industry in the form of user fees, with 
the remainder coming from general revenues. The CES manufacturers 
currently registered with FDA have annual revenues well under $100 
million, so they would likely be eligible for small business user fees, 
which are currently set at $59,705 for a premarket application (PMA or 
PDP) and $2,174 for a 510(k) submission (75 FR 45641 at 45643). Thus, 
user fees would likely cover $776,000 (= 13 x $59,705) of upfront and 
$86,000 (= 1.5 x [$59,705 -$2,174]) of subsequent annual rule-induced 
review costs. Because annual revenues for CES manufacturers are also 
below $30 million, CES manufacturers submitting first premarket 
applications may qualify for user fee waivers; such cases would 
increase the portion of FDA review costs coming from general revenues 
above the current estimates of $7.71 million upfront and $870,000 per 
subsequent year and decrease the anticipated rule-induced change in 
user fee collections.
    Table 1 of this document displays all quantified benefits and costs 
of the proposed rule. We reiterate that most of our estimates represent 
extreme upper bounds. For both benefits and costs, the likely effects 
of the rule would be much smaller than the estimates appearing in table 
1.

                              Table 1--Estimated Upper Bounds of Benefits and Costs
                                                  [$ thousands]
----------------------------------------------------------------------------------------------------------------
                                                         3% Discount rate                7% Discount rate
                                                 ---------------------------------------------------------------
                                                      Annual       Present value      Annual       Present value
----------------------------------------------------------------------------------------------------------------
Ongoing Benefit:
    Better-Informed Consumer Decisions..........           5,665          48,324           5,665          39,789
    Benefits: Ten-Year Total....................  ..............          48,324  ..............          39,789
Upfront Costs:
    Industry PMA or PDP Preparation.............          13,000          13,000          13,000          13,000
    User Fees...................................             776             776             776             776
    FDA Review, Net of User Fees................           7,710           7,710           7,710           7,710
Ongoing Costs:
    Industry PMA or PDP Preparation.............           1,484          12,656           1,484          10,421
    User Fees...................................              86             736              86             606
    FDA Review, Net of User Fees................             870           4,945             870           4,072
Costs: Ten-Year Total \1\.......................  ..............          39,823  ..............          36,584
----------------------------------------------------------------------------------------------------------------
\1\ Costs borne by consumers (in the form of welfare loss) are not estimated.

C. Impact on Small Entities

    The Regulatory Flexibility Act requires Agencies to prepare an 
initial regulatory flexibility analysis if a proposed rule would have a 
significant effect on a substantial number of small businesses, non-
profit organizations, local jurisdictions or other entities. Even 
though the producers of CES devices do tend to be small, only a very 
few entities participate in this market. FDA estimates that there are 
approximately 11 producers currently marketing CES devices; there may 
also be a handful of affiliated businesses that would be affected by 
the requirement for PMAs or PDPs. Therefore, FDA tentatively concludes 
that this proposed rule would not have a significant economic impact on 
a substantial number of small entities. We request comment on this 
issue.

D. Technical Appendix

    The supply-demand diagrams of figure 1 of this document illustrate 
the changes in the market for CES devices and services that would occur 
if the additional testing associated with class III pre-market approval 
were to reveal that CES devices are less safe and effective than 
consumers currently believe. In Panel A, the benefit of proposed 
requirement for PMAs or PDPs is represented by the shaded area below

[[Page 48068]]

the current market supply curve, above the better-informed, post-call 
for PMA demand curve (Demand1) and between the old and new quantities 
purchased (determined by the intersections of the pre- and post-call 
for PMAs or PDPs demand curves with the current supply curve or the 
vertical axis). A similar shaded benefit area appears in Panel B, but 
in that case, there is an offsetting loss (shown as the shaded triangle 
between the pre- and post-call for PMAs or PDPs supply curves) caused 
by CES producers passing on some costs related to PMAs and PDPs to 
consumers and consumers therefore purchasing even fewer CES devices or 
services than new information indicates they should. The overall 
benefit of the rule in Panel B is the difference between the areas of 
the Benefit and Loss triangles. In both panels of Figure 1, total CES 
spending by consumers, equal to the revenue collected by CES producers 
and shown as the rectangle LMNO, provides an upper bound on the amount 
of the shaded rule-induced social benefit. While total spending/revenue 
always provides an overestimate of the social benefit, the amount of 
the over-estimation may range from moderate, as in Panel A (the case in 
which CES products disappear from the market), to extreme, as in Panel 
B (the case in which there is continued use of at least some CES 
products).
[GRAPHIC] [TIFF OMITTED] TP08AU11.171

    If the additional testing associated with class III marketing 
approval increases consumers' confidence in the safety and 
effectiveness of CES devices, then demand for these products would 
increase, as depicted in figure 2 of this document. In this case, 
consumers currently purchase too few rather than too many CES devices 
and services as a result of incomplete information. The benefit to 
society of providing information can, as in Panel A of figure 1, be 
depicted graphically as the area between the pre-call for PMA or PDP 
supply curve and the post-call for PMA or PDP demand curve, and between 
the old and new quantities consumed (determined by the intersections of 
the pre- and post-call for PMA or PDP demand curves with the pre- and 
post-call for PMA or PDP supply curves), but because the revenue 
rectangle LMNO does not contain the shaded benefit area, FDA cannot in 
this case estimate a bound on the total social benefit.

[[Page 48069]]

[GRAPHIC] [TIFF OMITTED] TP08AU11.172

X. Federalism

    FDA has analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. FDA has determined that 
the proposed rule, if finalized, would not contain policies that would 
have substantial direct effects on the States, on the relationship 
between the National Government and the States, or on the distribution 
of power and responsibilities among the various levels of government. 
Accordingly, the Agency tentatively concludes that the proposed rule 
does not contain policies that have federalism implications as defined 
in the Executive order and, consequently, a federalism summary impact 
statement is not required.

XI. Paperwork Reduction Act of 1995

    This proposed rule refers to currently approved collections of 
information found in FDA regulations. These collections of information 
are subject to review by the Office of Management and Budget (OMB) 
under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). The 
collections of information in 21 CFR part 812 have been approved under 
OMB control number 0910-0078; the collections of information in 21 CFR 
part 814, subpart B, have been approved under OMB control number 0910-
0231; and the collections of information under 21 CFR part 801 have 
been approved under OMB control number 0910-0485.

XII. Proposed Effective Date

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

XIII. Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES), either electronic or written comments regarding this 
document. It is only necessary to send one set of comments. It is no 
longer necessary to send two copies of mailed comments. Identify 
comments with the docket number found in brackets in the heading of 
this document. Received comments may be seen in the Division of Dockets 
Management between 9 a.m. and 4 p.m., Monday through Friday.

XIV. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES), and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but we are not responsible 
for any subsequent changes to the Web sites after this document 
publishes in the Federal Register.)

1. Bystritsky A, L. Kerwin, J. Feusner, ``A Pilot Study of Cranial 
Electrotherapy Stimulation for Generalized Anxiety Disorder,'' 
Journal of Clinical Psychiatry, 69(3): 412-417, 2008.
2. Heffernan, Michael, ``The Effect of a Single Cranial 
Electrotherapy Stimulation on Multiple Stress Measures,'' The 
Townsend Letter for Doctors and Patients, 147: 60-64, 1995.
3. Overcash, Stephen J., ``Cranial Electrotherapy Stimulation in 
Patients Suffering From Acute Anxiety Disorders,'' American Journal 
of Electromedicine, 16(1): 49-51, 1999.
4. Voris, Marshall D, ``An Investigation of the Effectiveness of 
Cranial Electrotherapy Stimulation in the Treatment of Anxiety 
Disorders Among Outpatient Psychiatric Patients, Impulse Control 
Parolees and Pedophiles,'' Manuscript submitted for publication. 
Delos Mind/Body Institute, Dallas and Corpus Christi, TX: 1-19, 
1995.
5. Hyun J.K., Y.K. Woon, S.L. Yoon, et al., ``The Effect of Cranial 
Electrotherapy Stimulation on Preoperative Anxiety and Hemodynamic 
Responses.'' Korean Journal of Anesthesiology, 55: 657-61, 2008.
6. Winick, R.L., ``Cranial Electrotherapy Stimulation (CES): A Safe 
and Effective Low Cost Means of Anxiety Control in a Dental 
Practice,'' General Dentistry, 47(1): 50-55, 1999.
7. O'Connor M.E., F. Bianco, R. Nicholson, ``Meta-analysis of 
Cranial Electrostimulation (CES) in Relation to the Primary and 
Secondary Symptoms of Substance Withdrawal,'' Presented at the 12th 
annual meeting of the Bioelectromagnetics Society, June 14, 1991.
8. Klawansky S., A. Yeung, C. Berkey, et al., ``Meta-analysis of 
Randomized Controlled Trials of Cranial Electrostimulation,'' The 
Journal of Nervous and Mental Disease, 183(7): 478-485, 1995.

[[Page 48070]]

9. Manta: Vital Info on Small Businesses, http://www.manta.com, 
accessed June 11, 2010.
10. Blozan, Carl F. and Steven A. Tucker, ``Premarket Notifications: 
The First 24,000,'' Medical Device & Diagnostic Industry: 59-69, 
January 1986.
11. U.S. Department of Commerce, Bureau of Economic Analysis, 2010, 
National Income and Product Accounts Table 1.1.9., http://www.bea.gov/national/nipaweb/SelectTable.asp, accessed March 25, 
2011.
12. Geiger, Dale R. FY 2003 and 2004 Unit Costs for the Process of 
Medical Device Review, http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/ucm109216.pdf, 
accessed September 2005.

List of Subjects in 21 CFR Part 882

    Medical devices, Neurological devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, it is 
proposed that 21 CFR part 882 be amended as follows:

PART 882--NEUROLOGICAL DEVICES

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

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

    2. Section 882.5800 is amended by revising paragraph (c) to read as 
follows:


Sec.  882.5800  Cranial electrotherapy stimulator.

* * * * *
    (c) Date PMA or notice of completion of PDP is required. A PMA or 
notice of completion of a PDP is required to be filed with the Food and 
Drug Administration on or before [A DATE WILL BE ADDED 90 DAYS AFTER 
DATE OF PUBLICATION OF A FUTURE FINAL RULE IN THE FEDERAL REGISTER], 
for any cranial electrotherapy stimulator device that was in commercial 
distribution before May 28, 1976, or that has, on or before [A DATE 
WILL BE ADDED 90 DAYS AFTER DATE OF PUBLICATION OF A FUTURE FINAL RULE 
IN THE FEDERAL REGISTER], been found to be substantially equivalent to 
any cranial electrotherapy stimulator device that was in commercial 
distribution before May 28, 1976. Any other cranial electrotherapy 
stimulator device shall have an approved PMA or declared completed PDP 
in effect before being placed in commercial distribution.

    Dated: August 2, 2011.
Nancy K. Stade,
Deputy Director for Policy, Center for Devices and Radiological Health.
[FR Doc. 2011-19957 Filed 8-5-11; 8:45 am]
BILLING CODE 4160-01-P


