[Federal Register Volume 60, Number 164 (Thursday, August 24, 1995)]
[Rules and Regulations]
[Pages 43967-43969]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20960]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 882

[Docket No. 93N-0027]


Neurological Devices; Effective Date of Requirement for Premarket 
Approval of Cranial Electrotherapy Stimulators

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule 
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 (CES), a medical device. This action 
is being taken under the Medical Devices Amendments Act of 1976. 
Commercial distribution of this device must cease, unless a 
manufacturer or importer has filed with FDA a PMA for its version of 
the cranial electrotherapy stimulator device within 90 days of the 
effective date of this regulation.

EFFECTIVE DATE: August 24, 1995.
FOR FURTHER INFORMATION CONTACT: Janine M. Morris, Center for Devices 
and Radiological Health (HFZ-450), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-443-8517.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 4, 1979 (44 FR 51770), FDA 
published Sec. 882.5800 (21 CFR 882.5800) classifying the CES into 
class III (premarket approval). Section 882.5800 applies to (1) Any CES 
that was in commercial distribution before May 28, 1976, the date of 
enactment of the Medical Devices Amendments of 1976 (the amendments) 
(Pub. L. 94-295), and (2) any device that FDA has found to be 
substantially equivalent to the CES and that has been marketed on or 
after May 28, 1976.
    In the Federal Register of August 31, 1993 (58 FR 45865), FDA 
published a proposed rule to require the filing under section 515(b) of 
the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 360e(b)) 
of a PMA or a notice of completion of a PDP for the CES. In accordance 
with section 515(b)(2)(A) of the act, FDA included in the preamble to 
the proposal the agency's proposed findings with respect to the degree 
of risk of illness or injury designed to be eliminated or reduced by 
requiring the evice to meet the premarket approval requirements of the 
act, and the benefits to the public from use of the device (58 FR 45865 
at 45867). The August 31, 1993, proposed rule also provided an 
opportunity for interested persons to submit comments on the proposed 
rule and the agency's proposed findings. Under section 515(b)(2)(B) of 
the act (21 U.S.C. 360e(b)(2)(B)), FDA also provided an opportunity for 
interested persons to request a change in the classification of the 
device based on new information relevant to its classification. Any 
petition requesting a change in the classification of the cranial 
electrotherapy stimulator was required to be submitted by September 15, 
1993. The comment period closed on November 1, 1993.
    FDA received two petitions requesting a change in the 
classification of the device from class III to class II. FDA reviewed 
the petitions and found them deficient based on the lack of new 
information that was relevant to the device's classification. Each 
petitioner was sent a deficiency letter dated February 4, 1994, 
requiring a response to the reported deficiencies. Both petitions were 
deemed closed August 23, 1994, based on the petitioners' lack of 
response.

II. Summary and Analysis of Comments and FDA's Response

    The comments addressed issues relating to valid scientific studies 
pertaining to behavioral science and risks associated with the use of 
the CES device. (See 58 FR 46865 at 46867 and 46868 for a discussion of 
the benefits and risks of the CES device.) The comments are summarized 
as follows:
    1. A few comments were concerned that FDA's proposed findings were 
not evaluated by qualified behavioral scientists who could read and 
understand the literature. The comments noted that several references 
cited in the proposal do not meet the behavioral science criteria of a 
reliable ``dependent vector'' and would not have appeared in a 
knowledgeable behavioral science review. The comments further noted 
that the review conducted by a National Research Council panel on 
Electrosleep and Electroanesthesia did not include any behavioral 
scientists, and 90 percent of the studies reviewed by the panel were 
behavioral science studies.
    FDA recognizes that the proposed rule did not present critical 
reviews of all the literature. FDA also agrees that many of the studies 
in the literature do not meet the minimum criteria of behavioral 
science review. FDA has cited these publications only to show that the 
valid scientific evidence that is required to demonstrate the safety 
and effectiveness of CES devices in the form of well-controlled 
clinical studies is not presented in published data. FDA believes the 
data presented in the literature are not sufficient to fulfill the 
requirements of valid scientific evidence. Some of the studies were 
controlled studies that may have indicated some effect; however, 
information in the literature does provide a reasonable assurance that 
the device produces a reliable, repeated treatment effect. The few 
studies that presented controlled data were studying different clinical 
endpoints on a small number of patients so that an effect could not be 
established.
    2. One comment said that the risks to health identified in the 
proposed rule (worsening of the condition being treated, potential risk 
of seizure, skin irritation, and blurred vision) appear exaggerated, as 
discussed below:
    a. The comments said the risk of worsening of the condition being 
treated could easily be controlled by informing the patient when he or 
she should expect the treatment effect to occur. The comments stated 
that, for the case of a depressed patient, the perceived worsening 
effect is due to the patient's expectations for immediate effect.
    FDA agrees that the risk of worsening of the condition being 
treated might be controlled. However, until the CES is proved effective 
through valid scientific evidence, the agency believes that patients 
should not be subjected to the risk of worsening their condition by an 
ineffective treatment.
    b. One individual commented on personal involvement in a number of 
studies comprising a total of 800 patients where 26 of the patients 
were 

[[Page 43968]]
known seizure patients, and no seizures were reported.
    FDA observes that research relating electrical stimulation to 
epileptiform seizures has been studied only at higher levels of 
stimulation. The risk associated with the lower levels of electrical 
stimulation used with CES has not been systematically studied.
    c. The same comment stated that over 10,000 users of CES devices 
manufactured in the United States have never reported a burn.
    FDA agrees that there have been few reports of burns associated 
with CES devices; however, the device has the potential for causing 
burns. This risk appears to be unreasonable in the absence of 
established device effectiveness.
    d. One comment stated that blurred vision as a risk factor should 
not be considered because of a misconception about how electrodes are 
placed. The comment states that placing electrodes over the eyes was an 
early Russian technique that was abandoned in the United States by 
1970.
    FDA agrees that risks, such as blurring of vision, could be 
minimized; however, the existence of these potential risks is cited as 
evidence that premarket approval is appropriate, particularly in the 
absence of established device effectiveness. FDA believes that it is 
not clear whether placing of electrodes is the sole cause of blurred 
vision.
    3. One comment stated that the Weschler Adult Intelligence Scale 
and the Beta Examination Intelligence Quotient test are proven 
psychological measures of human intelligence.
    FDA intended to convey that many of the study measures of treatment 
effect are subjective and may not be considered valid as sole measures. 
However, FDA believes that it should review the validity of other 
measures including psychological measures, in the form of a PMA to 
provide reasonable assurance of the safety and effectiveness of this 
device.
    4. Another comment stated that the lack of followup data is not an 
adequate reason to invalidate a study reviewed in the literature 
because most of the studies were conducted by researchers who were not 
interested in study followup.
    FDA agrees that the absence of followup data should not be the sole 
reason not to accept clinical data on CES. However, FDA believes 
followup data are important in evaluating the long-term effects of CES 
devices and are components that should be considered to determine the 
safety and effectiveness of this device.
    5. One comment said that studies published by behavioral scientists 
include data that meet a statistical confidence of 95 percent and that 
their probability tables take into consideration whether the population 
is 5 or 500 subjects. The comment further stated that FDA was incorrect 
to say that the small sample size used in the study conducted by M. F. 
Weiss (58 FR 45865 at 45870 (Ref. 32)) would not demonstrate 
statistical significance for treatment effect.
    FDA believes that there was not sufficient information to determine 
that the Weiss study demonstrated a statistically significant effect. 
In addition, a single study of 10 subjects is not adequate to support a 
repeatable effect for the purposes of determining the safety and 
effectiveness of this device.
    6. One comment stated that FDA's review of the study by F. Ellison 
(58 FR 45865 at 45870 (Ref. 5)) in the proposal) was not complete. The 
comment said that Ellison's findings were that a single day of 
treatment was too short a duration to control withdrawal symptoms 
effectively and that 2 days of treatment were effective.
    FDA agrees that the purpose of the second experiment was to 
determine if 24 hours of treatment was sufficient to show an effect and 
that the purpose of the first experiment was to determine if there was 
a treatment effect after 48 hours. However, FDA believes the 
conclusions made in Ellison's study were based on the premise that CES 
was effective treatment. Based on the data that were presented, FDA 
could not draw the same conclusions.
    7. One comment stated that the references cited by V. Krauthamer 
(58 FR 45865 at 45870 (Refs. 14 and 15)) did not support the concept 
that electrical stimulation by CES is harmful.
    FDA did not cite these references to show that CES is harmful. The 
references by Krauthamer addressing the risk of potential adverse 
effects from electrical stimulation of the brain were cited to show 
that the effects of electrical stimulation are still unknown and have 
not been systematically evaluated, particularly for lower levels of 
stimulation.
    8. Several comments asserted that FDA did not review all the data 
available on CES devices. One comment referenced to four randomized 
controlled trials that were not cited in the references listed in the 
proposed rule. Another comment reported on data submitted to FDA in 
PMA's.
    FDA attempted to review all the published data available in the 
United States, and referenced in the proposed rule those the agency 
believes to be the most significant studies. Because the comments did 
not include copies of the four studies referred to, or citations to 
them, FDA cannot determine whether these studies were reviewed. 
Regarding the data submitted to FDA under a PMA, these data are 
considered proprietary information and are not intended for public 
release. However, they may be submitted as part of a PMA in response to 
this final rule.
    9. One comment submitted by a physician endorsed treating patients 
with addictions, and reported that CES has been a helpful adjunctive 
therapy in the treatment of psychoactive drug withdrawal syndromes.
    FDA believes that the comment that CES is helpful as an adjunctive 
therapy in drug withdrawal is anecdotal and does not represent valid 
scientific evidence.
    10. One comment objected to the fact that FDA did not make 
available to the public all references cited in the proposed rule at 
the Dockets Management Branch and requested an extension of the comment 
period for an additional 2 months.
    FDA considered comments received after the close of the official 
comment period and believes, therefore, that there was a sufficient 
comment period in which manufacturers, physicians, consumer 
organizations, researchers, and individuals could comment and present 
new information to determine whether FDA has a reasonable basis to 
require PMA's or notices of completed PDP's for the CES. Copies of the 
references cited were put on display at the Dockets Management Branch 
within 7 days of the proposed rule's publication.
    11. Two comments offered recommendations regarding the design of 
future studies to ensure high quality. One comment stated that 
published literature on CES devices has not shown through valid 
scientific evidence that these devices are effective.
    FDA agrees that the current literature is not adequate to support 
the safety and effectiveness of CES's and welcomes all recommendations 
for future studies to determine the safety and effectiveness of CES's.
    12. One comment stated that FDA's decision to require the 
submission of PMA's or notices of completed PDP's for CES devices is 
too costly and too time consuming.
    FDA has examined the economic consequences of the rule. The agency 
believes that only a small number of firms will be affected by this 
final rule. FDA's mission to protect the public health requires that 
the safety and 

[[Page 43969]]
effectiveness of these medical devices must be demonstrated.
    FDA believes that the comments presented insufficient information 
on which to base special controls that could assure safety and 
effectiveness. The agency concludes that its proposed findings and its 
conclusion discussed in the preamble to the proposed rule are 
appropriate. Accordingly, FDA is issuing a final regulation requiring 
premarket approval of the CES under section 515(b)(3) of the act.

III. Final Rule

    Under section 515(b)(3) of the act, FDA is adopting the findings as 
published in the preamble to the proposed rule and is issuing this 
final rule to require premarket approval of the generic type of device, 
the cranial electrotherapy stimulator device, by revising 
Sec. 882.5800(c).
    Under the final rule, a PMA or a notice of completion of a PDP is 
required to be filed with FDA within 90 days of the effective date of 
this regulation for any CES device that was in commercial distribution 
before May 28, 1976, or any device that FDA has found to be 
substantially equivalent to such a device on or before November 22, 
1995. An approved PMA or declared completed PDP is required to be in 
effect for any such device on or before 180 days after FDA files the 
application. Any other CES device that was not in commercial 
distribution before May 28, 1976, or that FDA has not found, on or 
before November 22, 1995, to be substantially equivalent to a CES 
device that was in commercial distribution before May 28, 1976, is 
required to have an approved PMA or declared completed PDP or declared 
completed in effect before it may be marketed.
    If a PMA or notice of completion of a PDP for a CES device is not 
filed on or before November 22, 1995, that device will be deemed 
adulterated under section 501(f)(1)(A) of the act (21 U.S.C. 
351(f)(1)(A)), and commercial distribution of the device will be 
required to cease immediately. The device may, however, be distributed 
for investigational use, if the requirements of the investigational 
device exemption (IDE) regulations (21 CFR part 812) are met.
    Under Sec. 812.2(d) (21 CFR 812.2(d)) of the IDE regulations, FDA 
hereby stipulates that the exemptions from the IDE requirements in 
Sec. 812.2(c)(1) and (c)(2) will no longer apply to clinical 
investigations of the CES device. Further, FDA concludes that 
investigational CES devices are significant risk devices as defined in 
Sec. 812.3(m) and advises that as of the effective date of 
Sec. 882.5800(c), requirements of the IDE regulations regarding 
significant risk devices will apply to any clinical investigation of a 
CES device. For any CES device that is not subject to a timely filed 
PMA or notice of completion of a PDP or notice of completion of a PDP, 
an IDE must be in effect under Sec. 812.20 on or before November 22, 
1995, or distribution of the device for investigational purposes must 
cease. FDA advises all persons currently sponsoring a clinical 
investigation involving the CES device to submit an IDE application to 
FDA no later than October 23, 1995, to avoid the interruption of 
ongoing investigations.

IV. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) and (e)(4) 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.

V. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs 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 final rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the final 
rule is not a significant regulatory action as defined by the Executive 
Order and so is not subject to review under the Executive Order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because PMA's for this device could have been 
required by FDA as early as March 4, 1982, and because firms that 
distributed this device prior to May 28, 1976, or whose device has been 
found to be substantially equivalent to the CES in commercial 
distribution before May 28, 1976, will be permitted to continue 
marketing cranial electrotherapy stimulators during FDA's review of the 
PMA or notice of completion of the PDP, the agency certifies that the 
final rule will not have a significant economic impact on a substantial 
number of small entities. Therefore, under the Regulatory Flexibility 
Act, no further analysis is required.

List of Subjects in 21 CFR Part 882

Medical devices.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
882 is amended as follows:

PART 882--NEUROLOGICAL DEVICES

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

    Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal 
Food, Drug, and Cosmetic Act (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 a PMA or notice of completion of a 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 November 22, 1995, for any cranial 
electrotherapy stimulator that was in commercial distribution before 
May 28, 1976, or that has on or before November 22, 1995, been found to 
be substantially equivalent to the cranial electrotherapy stimulator 
that was in commercial distribution before May 28, 1976. Any other 
cranial electrotherapy stimulator shall have an approved PMA or 
declared completed PDP in effect before being placed in commercial 
distribution.

    Dated: July 31, 1995.
D. B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 95-20960 Filed 8-23-95; 8:45 am]
BILLING CODE 4160-01-F