
[Federal Register Volume 81, Number 143 (Tuesday, July 26, 2016)]
[Rules and Regulations]
[Pages 48703-48707]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2016-17609]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 890

[Docket No. FDA-2000-N-0158]


Physical Medicine Devices; Reclassification of Iontophoresis 
Device Intended for Any Other Purposes

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 iontophoresis devices intended for any other 
purposes, which are preamendments class III devices (regulated under 
product code EGJ), into class II (special controls) and to amend the 
device identification to clarify that devices intended to deliver 
specific drugs are not considered part of this regulatory 
classification.

DATES: This order is effective on July 26, 2016.

FOR FURTHER INFORMATION CONTACT: Jismi Johnson, Center for Devices and 
Radiological Health, 10903 New Hampshire Ave., Bldg. 66, Rm. 1524, 
Silver Spring, MD 20993, 301-796-6424, jismi.johnson@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 (Pub. L. 101-629), the 
Food and Drug Administration Modernization Act

[[Page 48704]]

of 1997 (Pub. L. 105-115), the Medical Device User Fee and 
Modernization Act of 2002 (Pub. L. 107-250), the Medical Devices 
Technical Corrections Act (Pub. L. 108-214), the Food and Drug 
Administration Amendments Act of 2007 (Pub. L. 110-85), and the Food 
and Drug Administration Safety and Innovation Act (FDASIA) (Pub. L. 
112-144), among other amendments, established a comprehensive system 
for the regulation of medical devices intended for human use. Section 
513 of the FD&C Act (21 U.S.C. 360c) established three categories 
(classes) of devices, reflecting the regulatory controls needed to 
provide reasonable assurance of their safety and effectiveness. The 
three categories of devices are class I (general controls), class II 
(special controls), and class III (premarket approval).
    Under section 513(d) of the FD&C Act, devices that were in 
commercial distribution before the enactment of the 1976 amendments, 
May 28, 1976 (generally referred to as preamendments devices), are 
classified after FDA has: (1) Received a recommendation from a device 
classification panel (an FDA advisory committee); (2) published the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    A preamendments device that has been classified into class III and 
devices found substantially equivalent by means of premarket 
notification procedures (510(k)) 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 premarket approval application 
(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 or until the 
device is subsequently reclassified into class I or class II.
    Devices that were not in commercial distribution prior to May 28, 
1976 (generally referred to as postamendments devices) are 
automatically classified by section 513(f) of the FD&C Act into class 
III without any FDA rulemaking process. Those devices remain in class 
III and require premarket approval unless, and until, the device is 
reclassified into class I or II or FDA issues an order finding the 
device to be substantially equivalent, in accordance with section 
513(i) of the FD&C Act, to a predicate device that does not require 
premarket approval. The Agency determines whether new devices are 
substantially equivalent to predicate devices by means of premarket 
notification procedures in section 510(k) of the FD&C Act (21 U.S.C. 
360(k)) and part 807 (21 CFR part 807).
    On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA 
amended section 513(e) of the FD&C Act, changing the mechanism for 
reclassifying a device under that section from rulemaking to an 
administrative order.
    Section 513(e) of the FD&C Act governs reclassification of 
classified devices. This section provides that FDA may, by 
administrative order, reclassify a device based on ``new information.'' 
FDA can initiate a reclassification under section 513(e) of the FD&C 
Act or an interested person may petition FDA to reclassify a 
preamendments device. The term ``new information,'' as used in section 
513(e), includes information developed as a result of a reevaluation of 
the data before the Agency when the device was originally classified, 
as well as information not presented, not available, or not developed 
at that time. (See, e.g., Holland-Rantos Co. v. United States 
Department of Health, Education, and Welfare, 587 F.2d 1173, 1174 n.1 
(D.C. Cir. 1978); Upjohn v. Finch, 422 F.2d 944 (6th Cir. 1970); Bell 
v. Goddard, 366 F.2d 177 (7th Cir. 1966).)
    Reevaluation of the data previously before the Agency is an 
appropriate basis for subsequent action where the reevaluation is made 
in light of newly available authority (see Bell, 366 F.2d at 181; 
Ethicon, Inc. v. FDA, 762 F.Supp. 382, 388-391 (D.D.C. 1991)), or in 
light of changes in ``medical science'' (Upjohn, 422 F.2d at 951). 
Whether data before the Agency are old or new data, the ``new 
information'' to support reclassification under section 513(e) must be 
``valid scientific evidence,'' as defined in section 513(a)(3) of the 
FD&C Act and 21 CFR 860.7(c)(2). (See, e.g., General Medical Co. v. 
FDA, 770 F.2d 214 (D.C. Cir. 1985); Contact Lens Association v. FDA, 
766 F.2d 592 (D.C. Cir. 1985), cert. denied, 474 U.S. 1062 (1986).)
    FDA relies upon ``valid scientific evidence'' in the classification 
process to determine the level of regulation for devices. To be 
considered in the reclassification process, the ``valid scientific 
evidence'' upon which the Agency relies must be publicly available. 
Publicly available information excludes trade secret and/or 
confidential commercial information, e.g., the contents of a pending 
PMA. (See section 520(c) of the FD&C Act (21 U.S.C. 360j(c)).)
    Section 513(e)(1) of the FD&C Act sets forth the process for 
issuing a final order to reclassify a device under that section. 
Specifically, prior to the issuance of a final order reclassifying a 
device, the following must occur: (1) Publication of a proposed order 
in the Federal Register; (2) a meeting of a device classification panel 
described in section 513(b) of the FD&C Act; and (3) consideration of 
comments to a public docket.

II. Regulatory History of the Device

    FDA presented the complete regulatory history of these devices in 
the proposed order to reclassify iontophoresis devices for any other 
purposes, published in the Federal Register of September 22, 2014 (79 
FR 56532) (the ``proposed order''). The following are the most relevant 
pieces of the regulatory history of these devices. On August 28, 1979, 
the Agency published a proposed rule (44 FR 50520) for classification 
of all iontophoresis devices. On November 23, 1983, FDA issued a final 
rule in the Federal Register (48 FR 53032 at 53045) classifying 
iontophoresis devices into two different classes based on the device's 
intended use. Specifically, the rule classified iontophoresis devices 
into class II when intended to induce sweating for use in the diagnosis 
of cystic fibrosis or for other uses only when the labeling of the drug 
intended for use with the device bears adequate directions for the 
device's use with that drug (Sec.  890.5525(a) (21 CFR 890.5525(a))). 
These devices are currently under product code KTB. The rule classified 
iontophoresis devices into class III when intended for any other 
purposes (Sec.  890.5525(b)), but did not establish an effective date 
of requirement for premarket approval. These devices are currently 
under product code EGJ. In 2009, FDA published an order under section 
515(i) of the FD&C Act (the ``515(i) Order'') requiring manufacturers 
of remaining class III devices for which regulations requiring PMAs had 
not been issued, including iontophoresis devices (Sec.  890.5525(b)), 
to submit a summary of information concerning those devices by August 
7, 2009 (74 FR 16214, April 9, 2009).
    As discussed in the proposed order, FDA considered the available 
information on iontophoresis devices intended for any other purposes 
and concluded that these devices, which are prescription devices, could 
be reclassified to class II, subject to the special controls identified 
in the

[[Page 48705]]

proposed order, because there was sufficient information that these 
special controls, along with general controls, would provide reasonable 
assurance of safety and effectiveness. As required by section 513(e)(1) 
of the of the FD&C Act, FDA convened a meeting of a device 
classification panel described in section 513(b) of the FD&C Act, 
specifically the Orthopaedic and Rehabilitation Devices Panel (the 2014 
Panel), to discuss whether iontophoresis devices intended for any other 
purposes should be reclassified or remain in class III on February 21, 
2014 (Ref. 1). Please see the proposed order for additional information 
on the 2014 Panel. Ultimately, the panel concluded that sufficient 
information exists to establish special controls for these devices, and 
that special controls in combination with general controls could 
provide a reasonable assurance of safety and effectiveness; and thus, 
iontophoresis devices for any other purposes could be classified in 
class II.
    FDA received and has considered three sets of comments on this 
proposed order, as discussed in section III of this document. 
Therefore, FDA has met the requirements for issuing a final order under 
section 513(e)(1) of the FD&C Act. FDA is not aware of new information 
since the 2014 Panel meeting that would provide a basis for a different 
recommendation or finding.

III. Public Comments in Response to the Proposed Order

    In response to the proposed order, FDA received three sets of 
comments from various stakeholders. The comments and FDA's responses to 
the comments are summarized as follows.
    (Comment 1) One comment requested that iontophoresis devices 
intended for any other purposes remain classified in class III, and 
that FDA call for PMAs for these products. The commenter disagreed that 
general controls and special controls are sufficient to provide a 
reasonable assurance of safety and effectiveness because of, among 
other reasons, the commenter located, at the time of the 2014 Panel 
meeting, 40 adverse event reports for a 5-year period that implicated 
device malfunction, 12 of which include burns, in a search of the 
Manufacturer and User Facility Device Experience (MAUDE) database for 
iontophoresis devices intended for any other purposes. The commenter 
stated that manufacturing inspections during the PMA process would help 
ensure that iontophoresis devices are constructed properly and, 
therefore, be less likely to cause third degree burns and other 
injuries.
    (Response) FDA disagrees that iontophoresis devices intended for 
any other purposes should remain in class III and require PMA approval. 
As discussed in section V, ``Risks to Health,'' of the proposed order, 
these devices have certain risks to health; however, the Agency 
believes that those risks can be mitigated by the special controls. For 
example, the special controls include performance testing that will 
mitigate the risks of burns, insufficient or excessive drug delivery, 
and/or infection. Performance testing using a drug approved for 
iontophoretic delivery, or a solution, identified in the labeling, will 
ensure that device malfunction or use error is minimized. Additionally, 
performance testing will ensure that iontophoresis devices intended for 
any other purposes maintain a safe pH level to minimize burns from a 
large electrical current density or highly acidic solution. Based on 
FDA's review of the MAUDE database, the number of adverse event reports 
identified for iontophoresis devices intended for any other purposes 
has decreased over the last several years, supporting that the risk of 
injury is low. Furthermore, in the past decade, there have been no 
recalls for iontophoresis devices intended for any other purposes.
    (Comment 2) In addition, the commenter expressed concern that the 
special control requiring a labeling warning about adverse systemic 
effects was an insufficient safeguard because clinicians and patients 
may not see or read the label.
    (Response) FDA takes issue with this statement. As stated in the 
proposed order, iontophoresis devices are restricted to patient use 
only upon the authorization of a practitioner licensed by law to 
administer or use the device and the device identification in Sec.  
890.5525(b) has been revised to clarify that these are prescription 
devices in accordance with Sec.  801.109 (21 CFR 801.109). Per Sec.  
801.109(c), a prescription device, including iontophoresis devices 
intended for any other purposes, must include labeling that describes 
the indications and other information for use, such as methods, 
frequency and duration of administration, any relevant hazards, 
contraindications, side effects, and precautions under which the 
practitioners can use the device safely. Accordingly, clinicians will 
have access to and be aware of the warnings and precautions in the 
labeling, and as such, clinicians should be adequately informed of the 
risks associated with these devices. The clinician can inform the 
patients of the relevant risks. Therefore, the warning and precaution 
statements are an appropriate mitigation. FDA believes, therefore, that 
the special controls identified in this final order, in combination 
with general controls, will adequately mitigate the risks identified 
for iontophoresis devices intended for any other purposes and will 
provide a reasonable assurance of safety and effectiveness. FDA 
believes that iontophoresis devices may benefit patients by improving 
the noninvasive transdermal delivery of drugs or other solutions 
intended to treat various medical ailments or issues. As such, it is 
appropriate to reclassify these devices from class III (PMA) to class 
II (special controls). This is also the conclusion supported by the 
2014 Panel.
    (Comment 3) Two comments supported the reclassification of 
iontophoresis from class III to class II when these devices are 
intended for any other purposes. One comment, although overall 
supportive of reclassification, disagreed with the modified 
identification language and special controls. This comment asserted 
that the special controls, by requiring testing using a drug approved 
for iontophoretic delivery and labeling that contains language 
referring the user of the device to approved drug labeling, would 
create different regulatory paradigms for Sec.  890.5525(a) and (b), 
such that a new drug application (NDA) and 510(k) are needed for 
iontophoresis devices falling under paragraph (b) of the regulation, 
and that a 510(k) is needed for paragraph (a), although the devices are 
similar. The commenter uses iontophoresis devices that deliver 
pilocarpine for the diagnosis of cystic fibrosis, regulated under Sec.  
890.5525(a), as an example of this inconsistency.
    (Response) To the extent the commenter is raising issues related to 
products regulated under Sec.  890.5525(a), such products are not the 
subject of this reclassification; and as such, are not addressed here. 
However, we do note that the commenter's statement about two different 
regulatory paradigms is incorrect. As stated previously in this 
document and in the proposed order, whether an iontophoresis device 
falls into Sec.  890.5525(a) or (b), any drug that is intended to be 
used with these devices is required to have marketing authorization for 
iontophoretic administration of that drug. FDA intends to consider 
addressing the regulation of iontophoresis devices under Sec.  
890.5525(a) through a separate process.
    In addition, iontophoresis devices intended for any other purposes 
regulated under Sec.  890.5525(b) will need to comply with the 
applicable special

[[Page 48706]]

controls prior to entering the market. ``Any other purposes'' means 
that these devices are neither intended for use in the diagnosis of 
cystic fibrosis nor for use with a specific drug. Devices for any other 
purposes may include those intended for general iontophoretic delivery 
of drugs that are approved for that route of administration or intended 
for use with specific solutions. One example of an iontophoretic device 
for ``any other purposes'' is one indicated for use with tap water for 
treatment of hyperhidrosis.
    (Comment 4) The commenter also requested clarification on the 
identified risk of infection and the special control that states the 
patient-contacting elements of the device must be assessed for 
sterility.
    (Response) FDA believes that patient-contacting elements should be 
assessed for sterility if the device is labeled as sterile, and has 
clarified the special control in question (Sec.  890.5525(b)(2)(vi)) to 
specify such.

IV. The Final Order

    Based on the information discussed previously and in the preamble 
to the proposed order, the comments on the proposed order, a review of 
the MAUDE database, a review of current scientific literature, and 
panel deliberations (see the 2014 Panel transcript (Ref. 1)), FDA 
concludes that special controls, in conjunction with general controls, 
will provide reasonable assurance of the safety and effectiveness of 
iontophoresis devices intended for any other purposes. Under section 
513(e) of the FD&C Act, FDA is adopting its findings as published in 
the preamble to the proposed order, with the modification of the 
special control pertaining to sterility (Sec.  890.5525(b)(2)(vi)) to 
clarify that only devices labeled as sterile must have their patient-
contacting elements assessed for sterility. FDA is issuing this final 
order to reclassify iontophoresis devices intended for any other 
purposes from class III to class II and establish special controls by 
revising Sec.  890.5525(b).
    As noted previously, the identification for Sec.  890.5525(b) has 
been clarified to specify that devices intended to deliver specific 
drugs, including those drugs that may have adverse systemic effects, 
like fentanyl, are not considered part of this regulatory 
classification (Sec.  890.5525(b)(1)).
    Following the effective date of this final order, firms submitting 
a premarket notification (510(k)) for iontophoresis devices intended 
for any other purposes must comply with the applicable mitigation 
measures set forth in the codified special controls. This includes 
firms who are required to submit a new 510(k) under Sec.  807.81(a)(3) 
because the device is about to be significantly changed or modified. 
Additionally, a firm 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, must also comply with the 
special controls to remain legally on the market.
    Section 510(m) of the FD&C Act provides that FDA may exempt a class 
II device from the premarket notification requirements under section 
510(k) of the FD&C Act if FDA determines that premarket notification is 
not necessary to provide reasonable assurance of the safety and 
effectiveness of the devices. FDA has determined that premarket 
notification is necessary to provide reasonable assurance of safety and 
effectiveness of iontophoresis devices intended for any other purposes, 
and therefore, this device type is not exempt from premarket 
notification requirements.

V. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VI. Paperwork Reduction Act of 1995

    This final order refers to previously 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 part 807, subpart E, have been approved 
under OMB control number 0910-0120; and the collections of information 
under part 801 have been approved under OMB control number 0910-0485.
    In addition, FDA concludes that the labeling statement codified in 
this order does not constitute a ``collection of information'' under 
the PRA. Rather, the labeling statement is a public disclosure of 
information originally supplied by the Federal government to the 
recipient for the purpose of disclosure to the public (5 CFR 
1320.3(c)(2)).

VII. Codification of Orders

    Prior to the amendments by FDASIA, section 513(e) of the FD&C Act 
provided for FDA to issue regulations to reclassify devices. Although 
section 513(e) as amended requires FDA to issue final orders rather 
than regulations, FDASIA also provides for FDA to revoke previously 
promulgated regulations by order. FDA will continue to codify 
classifications and reclassifications in the Code of Federal 
Regulations (CFR). Changes resulting from final orders will appear in 
the CFR as changes to codified classification determinations or as 
newly codified orders. Therefore, under section 513(e)(1)(A)(i) of the 
FD&C Act, as amended by FDASIA, in this final order, we are revoking 
the requirements in Sec.  890.5525(b) related to the classification of 
iontophoresis devices intended for any other purposes as class III 
devices and codifying the reclassification of iontophoresis device 
intended for any other purposes into class II (special controls).

VIII. Reference

    The following reference is on display in the Division of Dockets 
Management (HFA-305) Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and is available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; it 
is also available electronically at http://www.regulations.gov. FDA has 
verified the Web site address, as of the date this document publishes 
in the Federal Register, but Web sites are subject to change over time.

1. The panel transcript and other meeting materials for the February 
21, 2014, Orthopedic and Rehabilitation Devices Panel are available 
on FDA's Web site at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/OrthopaedicandRehabilitationDevicesPanel/ucm386335.htm.

List of Subjects in 21 CFR Part 890

    Medical devices, Physical medicine devices.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, part 890 is 
amended as follows:

PART 890--PHYSICAL MEDICINE DEVICES

0
1. The authority citation for part 890 continues to read as follows:

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


0
2. In Sec.  890.5525 revise paragraph (b) and remove paragraph (c) to 
read as follows:


Sec.  890.5525  Iontophoresis device.

* * * * *

[[Page 48707]]

    (b) Iontophoresis device intended for any other purposes--(1) 
Identification. An iontophoresis device intended for any other purposes 
is a prescription device that is intended to use a current to introduce 
ions of drugs or non-drug solutions into the body for medical purposes 
other than those specified in paragraph (a) of this section, meaning 
that the device is not intended for use in diagnosis of cystic 
fibrosis, or a specific drug is not specified in the labeling of the 
iontophoresis device.
    (2) Classification. Class II (special controls). The device is 
classified as class II. The special controls for this device are:
    (i) The following performance testing must be conducted:
    (A) Testing using a drug approved for iontophoretic delivery, or a 
solution, if identified in the labeling, to demonstrate safe use of the 
device as intended;
    (B) Testing of the ability of the device to maintain a safe pH 
level; and
    (C) If used in the ear, testing of the device to demonstrate 
mechanical safety.
    (ii) Labeling must include adequate instructions for use, including 
sufficient information for the health care provider to determine the 
device characteristics that affect delivery of the drug or solution and 
to select appropriate drug or solution dosing information for 
administration by iontophoresis. This includes the following:
    (A) A description and/or graphical representation of the electrical 
output;
    (B) A description of the electrode materials and pH buffer;
    (C) When intended for general drug delivery, language referring the 
user to drug labeling approved for iontophoretic delivery to determine 
if the drug they intend to deliver is specifically approved for use 
with that type of device and to obtain relevant dosing information; and
    (D) A detailed summary of the device-related and procedure-related 
complications pertinent to use of the device, and appropriate warnings 
and contraindications, including the following warning:
    Warning: Potential systemic adverse effects may result from use of 
this device. Drugs or solutions delivered with this device have the 
potential to reach the blood stream and cause systemic effects. 
Carefully read all labeling of the drug or solution used with this 
device to understand all potential adverse effects and to ensure 
appropriate dosing information. If systemic manifestations occur, refer 
to the drug or solution labeling for appropriate action.
    (iii) Appropriate analysis/testing must demonstrate electromagnetic 
compatibility, electrical safety, thermal safety, and mechanical 
safety.
    (iv) Appropriate software verification, validation, and hazard 
analysis must be performed.
    (v) The elements of the device that may contact the patient must be 
demonstrated to be biocompatible.
    (vi) The elements of the device that may contact the patient must 
be assessed for sterility, for devices labeled as sterile.
    (vii) Performance data must support the shelf life of the elements 
of the device that may be affected by aging by demonstrating continued 
package integrity and device functionality over the stated shelf life.

    Dated: July 20, 2016.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2016-17609 Filed 7-25-16; 8:45 am]
BILLING CODE 4164-01-P


