[Federal Register Volume 85, Number 159 (Monday, August 17, 2020)]
[Proposed Rules]
[Pages 49986-49994]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2020-17543]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 890
[Docket No. FDA-2020-N-1053]
Physical Medicine Devices; Reclassification of Non-Invasive Bone
Growth Stimulators
AGENCY: Food and Drug Administration, Health and Human Services (HHS).
ACTION: Proposed amendment; proposed order; request for comments.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to
reclassify non-invasive bone growth stimulators, postamendments class
III devices (product codes LOF and LPQ), into class II (special
controls), subject to premarket notification. FDA is also proposing a
new device classification with the name ``non-invasive bone growth
stimulators'' along with the proposed special controls that the Agency
believes are necessary to provide a reasonable assurance of safety and
effectiveness of these devices. FDA is proposing this reclassification
on its own initiative. If finalized, this order will reclassify these
devices from class III (premarket approval) to class II (special
controls) and reduce the regulatory burdens associated with these
devices, as these devices will no longer be required to submit a
premarket approval application (PMA), but are subject to premarket
notification (510(k)) requirements and general and special controls.
DATES: Submit either electronic or written comments on the proposed
order by October 16, 2020. Please see section XII of this document for
the proposed effective date when the new requirements apply and for the
proposed effective date of a final order based on this proposed order.
ADDRESSES: You may submit comments as follows. Please note that late,
[[Page 49987]]
untimely filed comments will not be considered. Electronic comments
must be submitted on or before October 16, 2020. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of October 16, 2020. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal Rulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2020-N-1053 for ``Physical Medicine Devices; Reclassification of
Non-Invasive Bone Growth Stimulators.'' Received comments, those filed
in a timely manner (see ADDRESSES), will be placed in the docket and,
except for those submitted as ``Confidential Submissions,'' publicly
viewable at https://www.regulations.gov or at the Dockets Management
Staff between 9 a.m. and 4 p.m., Monday through Friday.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://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 Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Jesse Muir, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. 4508, Silver Spring, MD 20993, 240-402-6679,
[email protected].
SUPPLEMENTARY INFORMATION:
I. Background--Regulatory Authorities
The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended,
establishes a comprehensive system for the regulation of medical
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C.
360c) established three categories (classes) of devices, reflecting the
regulatory controls needed to provide reasonable assurance of their
safety and effectiveness. The three categories of devices are class I
(general controls), class II (general controls and special controls),
and class III (general controls and premarket approval).
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)(1) 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: (1) FDA
reclassifies the device into class I or II or (2) 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. FDA 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), subpart E, of the regulations.
A postamendments device that has been initially classified in class
III under section 513(f)(1) of the FD&C Act may be reclassified into
class I or class II under section 513(f)(3) of the FD&C Act. Section
513(f)(3) of the FD&C Act provides that FDA acting by administrative
order, can reclassify the device into class I or class II on its own
initiative, or in response to a petition from the manufacturer or
importer of the device. To change the classification of the device, the
proposed new class must have sufficient regulatory controls to provide
reasonable assurance of the safety and effectiveness of the device for
its intended use.
Reevaluation of the data previously presented before the Agency is
an appropriate basis for subsequent action, where the reevaluation is
made in light of newly available regulatory authority (see Bell v.
Goddard, 366 F.2d 177, 181 (7th Cir. 1966); Ethicon, Inc. v. FDA, 762
F. Supp. 382, 388-391 (D.D.C. 1991)) or in light of changes in
``medical science'' (Upjohn v. Finch, 422 F.2d 944, 951 (6th Cir.
1970)). Whether data before the Agency are old or new, the ``new
information'' to support reclassification under 513(f)(3) must be
``valid scientific evidence'', as defined in section 513(a)(3) of the
FD&C Act and Sec. 860.7(c)(2) (21 CFR 860.7(c)(2)). (See, e.g.,
General Medical Co. v. FDA, 770 F.2d 214 (D.C. Cir. 1985); Contact Lens
Assoc. v. FDA, 766 F.2d 592 (D.C. Cir.
[[Page 49988]]
1985), cert. denied, 474 U.S. 1062 (1986).)
FDA relies upon ``valid scientific evidence,'' as defined in
section 513(a)(3) of the FD&C Act and Sec. 860.7(c)(2), 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
520(h)(4) of the FD&C Act provides that FDA may use, for
reclassification of a device, certain information in a PMA 6 years
after the application has been approved (Ref. 1). This includes
information from clinical and preclinical tests or studies that
demonstrate the safety or effectiveness of the device, but does not
include descriptions of methods of manufacture or product composition
and other trade secrets.
In accordance with section 513(f)(3) of the FD&C Act, FDA is
issuing this proposed order to reclassify non-invasive bone growth
stimulator devices, postamendments class III devices, into class II
(special controls), subject to premarket notification because FDA
believes the standard in section 513(a)(1)(B) of the FD&C Act is met as
there is sufficient information to establish special controls, which in
addition to general controls, will provide reasonable assurance of the
safety and effectiveness of the device.\1\
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\1\ In December 2019, FDA began adding the term ``Proposed
amendment'' to the ``ACTION'' caption for these documents, typically
styled ``Proposed order'', to indicate that they ``propose to
amend'' the Code of Federal Regulations. This editorial change was
made in accordance with the Office of Federal Register's (OFR)
interpretations of the Federal Register Act (44 U.S.C. chapter 15),
its implementing regulations (1 CFR 5.9 and parts 21 and 22), and
the Document Drafting Handbook.
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Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the premarket notification requirements under section
510(k) of the FD&C Act, if the Agency determines that premarket
notification is not necessary to reasonably assure the safety and
effectiveness of the device. FDA has determined that premarket
notification is necessary to reasonably assure the safety and
effectiveness of non-invasive bone growth stimulator devices.
Therefore, the Agency does not intend to exempt these proposed class II
devices from premarket notification (510(k)) submission as provided
under section 510(m) of the FD&C Act.
II. Regulatory History of Non-Invasive Bone Growth Stimulator Devices
In accordance with section 513(f)(1) of the FD&C Act, non-invasive
bone growth stimulator devices were automatically classified into class
III because they were not introduced or delivered for introduction into
interstate commerce for commercial distribution before May 28, 1976,
and have not been found substantially equivalent to a device placed in
commercial distribution after May 28, 1976, which was subsequently
classified or reclassified into class II or class I. Therefore, the
device is subject to PMA requirements under section 515 of the FD&C Act
(21 U.S.C. 360e).
Accordingly, on November 6, 1979, FDA approved a PMA for the Bio
Osteogen System 204 (P790002) (Ref. 2). Since that time, five
additional original PMAs have been approved for non-invasive bone
growth stimulators (P850007, P850022, P900009, P910066, and P030034).
On February 9, 2005, FDA received a reclassification petition dated
February 7, 2005, submitted by RS Medical Corporation, requesting that
FDA reclassify certain non-invasive bone growth stimulators from class
III to class II (Ref. 3). As stated in the Notice of Panel
Recommendation discussed further below, ``the petition was submitted
under section 513(e) of the act but FDA . . . review[ed] the petition
under section 513(f)(3) of the act because that section contain[ed] the
appropriate procedures for reclassification of postamendments devices''
(72 FR 1951 at 1952, January 17, 2007). FDA requested additional
information and the petitioner amended the petition on November 30,
2005 (``amended petition''). In accordance with the FD&C Act and
regulations, FDA referred the petition, as amended, to the FDA Advisory
Committee, specifically the Orthopaedic and Rehabilitation Devices
Panel (``the 2006 Panel'') for its recommendations on the requested
reclassification.
On June 2, 2006, the 2006 Panel deliberated on the information in
RS Medical's petition; the presentations made by RS Medical, FDA, and
members of the public; and their own experience with certain non-
invasive bone growth stimulators (Ref. 4).
The 2006 Panel identified the following risks to health associated
with non-invasive bone growth stimulators: Electric shock; burn; skin
irritation and/or allergic reaction; inconsistent or ineffective
treatment; adverse interaction with electrical implants; adverse
interactions with internal/external fixation devices; and biological
risks. The 2006 Panel did not specifically address risks associated
with ultrasound-based devices, as these were outside the scope of RS
Medical's petition; however, as discussed below, based upon FDA's
review of information since the Panel meeting, the risks identified
with ultrasound-based devices, along with their reported benefits, are
comparable to those of non-invasive bone growth stimulators
incorporating other modalities.
The majority of the 2006 Panel recommended that non-invasive bone
growth stimulators should be retained in class III because there was
insufficient information in the petition by RS Medical to establish
that special controls in conjunction with general controls would
provide a reasonable assurance of the safety and effectiveness of the
device. Specifically, the Panel recommended that the proposed special
controls by RS Medical were sufficient to control for the risk of
electric shock, burn, skin irritation, and/or allergic reaction;
adverse interaction with electrical implants; adverse interactions with
internal/external fixation devices; and biological risks. However, the
Panel believed that there was insufficient evidence presented by RS
Medical to control for the risk of inconsistent or ineffective
treatment because there is a lack of knowledge about how waveform
characteristics (e.g., pulse duration, amplitude, power, frequency),
including potential modifications to the device, affect the clinical
response to treatment. The Panel requested additional clinical data
and/or special controls, which was not adequately devised by the
petitioner, to control for the risk of inconsistent or ineffective
treatment.
FDA concurred with the 2006 Panel's recommendation, and similarly
believed that RS Medical's petition was inadequate in that FDA had
concerns about the petitioner's proposed special controls to control
the risk of inconsistent or ineffective treatment. In the Federal
Register of January 17, 2007 (72 FR 1951), FDA published a Notice of
Panel Recommendations (``the 2007 Notice''), as referenced above.
In a letter dated April 2, 2007, RS Medical requested that its
petition be withdrawn (Ref. 5). On July 10, 2007, FDA granted RS
Medical's request for withdrawal of the petition and did not take any
further action on the petition (Ref. 6). FDA has not received any
subsequent petition requesting reclassification of these devices.
Subsequently, as part of the Center for Devices and Radiological
Health's 2014-2015 strategic priority, ``Strike the Right Balance
Between Premarket and Postmarket Data Collection,'' a
[[Page 49989]]
retrospective review of all PMA product codes with active PMAs approved
prior to 2010 was conducted to determine whether, based on our current
understanding of the technology, certain devices could be reclassified
(down-classified). On April 29, 2015, FDA published a document in the
Federal Register identifying certain product codes as potential
candidates for reclassification (80 FR 23798), including non-invasive
bone growth stimulators under product codes LOF and LPQ, from class III
to class II (Ref. 7). One comment was received in response to this
proposal for reclassification of LOF and LPQ; this comment did not
support FDA's intention to reclassify these devices, citing the
concerns discussed during the 2006 Panel. This comment was considered
in development of this proposed order. Note that invasive bone growth
stimulators, designated under product code LOE, are outside the scope
of this proposed reclassification. As noted in the 2006 Panel, invasive
bone growth stimulator devices have added risks compared to non-
invasive bone growth stimulators, and therefore would require a
separate classification discussion. Furthermore, invasive bone growth
stimulators were also considered as a part of the aforementioned PMA
retrospective review and FDA determined that these devices should
remain as class III (Ref. 8). Therefore, FDA will continue to regulate
invasive bone growth stimulators as a class III device, subject to PMA
requirements.
While RS Medical's petition inadequately addressed all of the risks
associated with non-invasive bone growth stimulators for
reclassification, FDA is, on its own initiative, proposing to
reclassify these devices from class III to class II, and believes that
sufficient information exists to establish special controls, as
identified in this proposed order, that, together with general
controls, can provide a reasonable assurance of safety and
effectiveness for this device type. Additionally, RS Medical in its
petition excluded use of these devices as an adjunct to cervical fusion
surgery in patients at high risk for nonfusion, as well as for use in
congenital pseudarthrosis. Based upon the review of the evidence and
FDA's ability to establish special controls, FDA believes these
indications that have been approved for currently marketed non-invasive
bone growth stimulator devices should be included in this proposed
reclassification.
III. Device Description
Non-invasive bone growth simulators, currently designated under
product codes LOF and LPQ, are typically composed of a waveform
generator and transducer (e.g., coils, electrodes, and/or ultrasound
transducers). Patient-contacting surfaces include the transducers, lead
wires, and the device outer casing.
Non-invasive bone growth stimulators utilize an electrical
component to produce an output electrical, magnetic, or ultrasonic
waveform that is delivered to a treatment site via a non-invasively
applied transducer (e.g., electromagnetic coil or ultrasound
transducer) or electrodes (e.g., capacitor plates). The device also
incorporates an internal means to monitor the output waveform and
delivery of treatment, and to provide visual and/or audible alarms to
alert the user of improper device function. The induced electrical and/
or magnetic fields are generated using one of the following modalities:
Capacitive coupling (CC), in which a pair of electrodes
are placed on the skin such that a current can be driven across the
target site;
pulsed electromagnetic fields (PEMF), in which a modulated
electromagnetic field is generated near the treatment site though an
external coil; or
combined magnetic fields (CMF), in which a coil generates
a combination of a static and pulsed magnetic field near the treatment
site.
The ultrasonic waveform is generated using:
Low intensity pulsed ultrasound (LIPUS), in which pulsed
ultrasonic signals are generated using ultrasonic transducers.
The non-invasive nature of the device obviates the need for sterile
components; however, patient-contacting surfaces should be capable of
being cleaned as needed and biocompatibility must be ensured.
Non-invasive bone growth stimulators are generally intended to
promote osteogenesis as adjunct to primary treatments for fracture
fixation or spinal fusion. The indications for use for this device type
depend on the specific device characteristics, but have included:
Treatment of an established non-union secondary to trauma
of the appendicular system,
treatment of congenital pseudarthrosis,
treatment of failed fusions of the appendicular system,
early treatment of certain fresh fractures, and
as an adjunct to lumbar or cervical spinal fusion.
In addition, non-invasive bone growth stimulators are currently
prescription use only devices under Sec. 801.109 (21 CFR 801.109).
IV. Proposed Reclassification
In accordance with section 513(f)(3) of the FD&C Act and 21 CFR
part 860, subpart C, FDA is proposing to reclassify non-invasive bone
growth stimulator devices under product codes LOF and LPQ from class
III into class II. This includes devices that generate electrical or
magnetic fields using CC, PEMF, and CMF, and ultrasonic signals.
FDA believes that there is sufficient information available by way
of FDA's accumulated experience with these devices from review of
premarket submissions, peer-reviewed literature, medical device reports
(MDRs), and recalls to understand the risks associated with these
devices to establish special controls that effectively mitigate the
risks to health identified in section V. In this proposed order, the
Agency has identified the special controls under section 513(a)(1)(B)
of the FD&C Act that, together with general controls, would provide a
reasonable assurance of the safety and effectiveness for non-invasive
bone growth stimulators to be in class II. Absent the special controls
identified in this proposed order, general controls applicable to this
device type are insufficient to provide reasonable assurance of safety
and effectiveness of the device.
FDA is proposing to create a classification regulation for non-
invasive bone growth stimulators, which would include devices
designated under product codes LOF and LPQ. Under this proposed order,
if finalized, a non-invasive bone growth stimulator will be identified
as a prescription device. As such, the prescription device must satisfy
prescription labeling requirements (see Sec. 801.109, Prescription
devices). Prescription devices are exempt from the requirement for
adequate directions for use for the layperson under section 502(f)(1)
of the FD&C Act (21 U.S.C. 352(f)(1)) and 21 CFR 801.5, as long as the
conditions of Sec. 801.109 are met. In this proposed order, if
finalized, the Agency has identified the special controls under section
513(a)(1)(B) of the FD&C Act that, together with general controls, will
provide a reasonable assurance of the safety and effectiveness for non-
invasive bone growth stimulator devices.
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
[[Page 49990]]
to provide reasonable assurance of the safety and effectiveness of the
device. For non-invasive bone growth stimulators, FDA has determined
that premarket notification is necessary to provide reasonable
assurance of the safety and effectiveness of the device. Therefore, FDA
does not propose to exempt these proposed class II devices from 510(k)
requirements. If this order is finalized, persons who intend to market
this type of device would need to submit to FDA a 510(k) and receive
clearance prior to marketing the device.
V. Risks to Health
Based on available information for non-invasive bone growth
stimulators, including the 2005 reclassification petition request from
RS Medical Corp, input from the 2006 Panel, data in PMA applications
P030034, P850022/S009, and P910066/S011 available to FDA under section
520(h)(4) of the FD&C Act, published literature, and postmarket
experience associated with use of these devices, FDA identifies the
following risks to health associated with non-invasive bone growth
stimulators:
a. Failure or delay of osteogenesis--A patient could receive
ineffective treatment, contributing to failure or delay of osteogenesis
that may lead to clinical symptoms (e.g., pain) and the need for
surgical interventions. Ineffective treatment could be a result of
various circumstances (e.g., inadequate therapeutic signal output or
device malfunction or misuse).
b. Burn--A patient or health care professional could be burned from
the use and operation of the device. This could be a result of various
circumstances including device malfunction (e.g., electrical fault) or
misuse of the device (e.g., use while sleeping).
c. Electrical shock--A patient or health care professional could be
shocked from the use and operation of the device. This could be a
result of various circumstances including device malfunction (e.g.,
electrical fault) or misuse of the device (e.g., use of alternating
current source during treatment).
d. Electromagnetic interference (EMI)--A patient with electrically
powered implants (such as cardiac pacemakers, cardiac defibrillators,
and neurostimulators) could experience an adverse interaction with the
implanted electrical device via EMI or radiofrequency interference.
e. Adverse tissue reaction--A patient could experience skin
irritation and/or allergic reaction associated with the use and
operation of the device via the use of non-biocompatible device
materials.
f. Adverse interaction with internal/external fixation devices--The
signal output could be impacted by certain metallic internal or
external fixation devices leading to inadequate treatment signals,
device malfunction, or tissue damage.
g. Adverse biologic effects--A patient may experience adverse
biologic effects resulting from prolonged exposure to the treatment
signal via biologic interaction with the treatment signal at a cellular
level. Excessive energy transmission could cause tissue damage or
aberrant tissue behavior if signal output parameters exceed established
safety thresholds.
The risks to health identified within this proposed order are
consistent with those identified in the 2005 reclassification petition,
as amended. The 2006 Panel agreed with these identified risks; however,
in some cases the risk or accompanying description was reworded for
clarity in this proposed order (e.g., ``inconsistent treatment or
ineffective treatment'' is described in terms of risk to health, which
may entail ``failure or delay in osteogenesis''). Also, the risk of
adverse biologic effects previously specified risks of carcinogenicity,
genotoxicity, mutagenicity, and teratological effects. The petitioner
notes in the amended petition that ``. . . the evidence points to lack
of genotoxic, carcinogenic, and teratologic potential of the subject
waveforms,'' which is corroborated by the lack of such reports
identified in the literature. Although FDA similarly has found a lack
of such reports, it considers this risk more generally as potential
deleterious effects at the tissue or cellular level due to signal
output parameters that exceed established safety thresholds.
VI. Summary of Reasons for Reclassification
FDA believes that non-invasive bone growth stimulator devices,
which are intended to promote osteogenesis as an adjunct to primary
treatments for fracture fixation or spinal fusion, should be
reclassified from class III to class II and that there is sufficient
information to establish special controls for the risks identified in
section V which, in addition to general controls, can provide
reasonable assurance of safety and effectiveness.
Specifically, FDA proposes to require clinical performance data as
a special control to address the risk of failure or delay of
osteogenesis. FDA review of the literature suggests a high variability
of treatment efficacy, depending on therapeutic signal and anatomic
location. This would also address the main concern cited by the 2006
Panel and FDA with RS Medical's proposal, which led to the
recommendation to retain non-invasive bone growth stimulators in class
III, and various comments received in response to the 2007 Notice.
FDA's proposal would require that clinical performance of any non-
invasive bone growth stimulator device be evaluated in support of the
intended use. Rather than prescribe specific study requirements, FDA's
proposal would allow for flexibility in study design and the level of
clinical evidence needed by taking into consideration certain
parameters, e.g., the intended use, treatment population, and
technological characteristics of the device, including any similarities
between the device and legally marketed predicate device, as
appropriate.
VII. Summary of Data Upon Which the Reclassification Is Based
The available evidence demonstrates that there are probable health
benefits derived from the use of these devices, and that the nature and
incidence of risks are well known so that special controls can be
established to adequately mitigate the risks to health. FDA is
proposing a single device class for non-invasive bone growth
stimulators, considering that FDA did not identify any unique risks
associated with the different modalities included in this proposed
order. FDA has considered and analyzed the following: Data in PMA
applications P030034, P850022/S009, and P910066/S011 available to FDA
under section 520(h)(4) of the FD&C Act; information presented at the
2006 Panel concerning RS Medical's petition to down-classify certain
non-invasive bone growth stimulators (Ref. 3) and the 2007 Notice;
peer-reviewed articles that discussed the use of, as well as the
probable benefits and risks of these devices; reported adverse events
identified through a search of FDA's Medical Device Reporting (MDR)
system; and a review of any recalls associated with these devices
through a search of FDA's Medical Device Recall database.
In accordance with the ``6-year rule'' described in section
520(h)(4) of the FD&C Act, FDA considered data contained in three
original PMAs or supplements, P030034, P850022/S009, and P910066/S011,
approved for non-invasive bone growth stimulators (Refs. 9 to 11).
These PMAs/supplements include three different device modalities: A
PEMF device (P030034), a CC device (P850022/S009), and a CMF device
(P910066/S011). In review of the reported clinical data in the summary
of
[[Page 49991]]
safety and effectiveness data documents (SSEDs), the studies conducted
in support of these devices include a total study size of 831 enrolled
subjects. The adverse event profile for the devices in each study were
similar to the control group, with a similar distribution of event
types. With regards to benefit, the clinical data reported in the SSEDs
demonstrate an improved rate of bone fusion compared to placebo
controls, with an 83.6 percent vs. 68.6 percent fusion rate at 6 months
in P030034 (cervical spine), an 85 percent vs. 75 percent clinical
success shown in P850022/S009 (lumbar spine), and a 67 percent vs. 43
percent fusion rate at 9 months in P910066/S011 (lumbar spine).
Further, FDA performed a literature review to evaluate data related
to non-invasive bone growth stimulator devices, including studies up to
the date of the 2006 Panel, as well as any new clinical information
published since the 2006 Panel.
Literature published at the time of the 2006 Panel includes a 1953
seminal paper on the use of electrical signals to stimulate bone
formation by Yasuda, that reported bone formation in rabbits exposed to
direct current (DC) stimulation (Ref. 12). In the following decades,
other researchers expanded on this finding in animal and clinical
models. In a canine study, a DC stimulation was shown to cause complete
ossification of the femoral medullary canal (Ref. 13). The first
clinical case report demonstrated that electrical stimulation could
treat a non-union fracture (Ref. 14). An early publication regarding
the effects of DC stimulation on spinal fusion was published by Dwyer
(Ref. 15). Another early clinical study published by Becker, et al.
showed successful fracture fusion with a success rate of 77 percent
(Ref. 16).
In the 1990s and early 2000s, several literature articles were
identified assessing the effects of non-invasive bone growth
stimulators on various anatomic locations. These studies generally
included various therapeutic modalities (magnitude, frequency,
duration, etc.) and demonstrated varying results regarding the efficacy
of these treatments. In two studies of PEMF devices, Basset and Schink-
Ascani (Ref. 17) found a 72 percent fusion rate in patients with
congenital pseudarthrosis of the tibia, and in a study of non-unions of
the scaphoid, Adams, et al. (Ref. 18) reported a fusion rate of 69
percent, as a followup to an earlier study that found a fusion rate of
80 percent. When looking at the rate of compliance of PEMF devices as a
factor of effectiveness, Garland, et al. (Ref. 19) found that fusion
rates ranged from 35.7 percent to 80 percent, depending on how often
the devices were used. In studies of CC devices, fusion rates in long
bones varied from 60 percent (Ref. 20), 68.8 percent (Ref. 21), and
72.7 percent (Ref. 22), to no difference between treatment and a
placebo-treated group in a study by Fourie and Bowerbank (Ref. 23).
While there was a large range of observed efficacies, there was no
reporting of treatment-related adverse events. These reported
variabilities in efficacy and low adverse event rates were consistent
with the findings by the 2006 Panel.
FDA performed a systematic review of published literature to
identify any new clinical findings since the 2006 Panel. FDA identified
14 papers that included a combination of retrospective and prospective
studies. For studies that assessed medical or insurance claims
databases, radiographs were not always available to determine actual
fusion. Instead, results were presented in terms of healing rate based
on patient records or reported outcomes. When radiographs were
available and analyzed to assess union, results were reported as fusion
rate.
Phillips, et al. (Ref. 24) looked at registry data of 2,370
subjects who were treated with OL1000 (DJO), a CMF device, at various
fracture sites and reported an average healing rate of 75.1 percent
(ranging from 57.2 percent in the humerus to 89.7 percent in the finger
phalanx). DeVries, et al. (Ref. 25) also evaluated the OL1000 device in
a retrospective analysis of 144 subjects, finding a fusion rate of 57.1
percent in tibiotalocalcaneal fusions of the ankle.
With respect to LIPUS, Zura, et al. (Refs. 26 and 27) published two
papers evaluating subjects in the Exogen (Bioventus) Post Market
Registry. One of the studies assessed how various patient risk factors
affected healing rate in 4,190 subjects. The study demonstrated an
overall healing rate of 95.7 percent, and in another single arm study
of 767 subjects, showed a healing rate varying from 81.8 percent to
87.9 percent depending on fracture site. Nolte, et al. (Ref. 28)
evaluated the Exogen registry in conjunction with a medical claims
database to examine metatarsal fractures and reported a healing rate of
97.4 percent overall, while Elvey, et al. (Ref. 29) evaluated 26 cases
with use of Exogen in hand and wrist non-unions, and found a fusion
rate of 54 percent to 58 percent. In two smaller studies of the Exogen
device, Majeed, et al. (Ref. 30) and Mizra, et al. (Ref. 31) both
evaluated foot and ankle fractures and found 78.7 percent and 67
percent fusion rate in a 47 and 18 patient study, respectively. Biglari
(Ref. 32) also performed an observational study using the Exogen device
and found a much lower fusion rate of 32.8 percent in 60 subjects
having existing non-unions of various long bones.
For PEMF devices, a retrospective study by Coric, et al. (Ref. 33)
on the effects of the CervicalStim (Orthofix) device on 593 subjects
showed a 73.2 percent fusion rate in the cervical spine at 6 months. In
a single arm prospective study by Assiotis, et al. (Ref. 34), a 77.3
percent fusion rate in the tibia was demonstrated with use of the
Physiostim (Orthofix). Murray and Pethica (Ref. 35) performed a 1,382-
subject retrospective study of use of the EBI device (Zimmer Biomet)
for non-unions of the scaphoid, tibia, and fibula, and while an
assessment of healing rates was not performed, the data showed
reduction in time to healing between 35 percent and 40 percent when the
device was used as prescribed.
In addition, two randomized control studies on PEMF devices were
conducted by Foley, et al. (Ref. 36) and by Streit, et al. (Ref. 37).
Foley evaluated 323 subjects using the Orthofix CervicalStim device in
cervical fusion and found an 83.6 percent fusion rate in the treatment
group compared to a 68.6 percent fusion rate in the control group, with
no difference in pain scores or adverse events between groups. Streit,
et al. performed a small, eight subject clinical study using the EBI
device to treat non-unions of the fifth metatarsal and found the time
to fusion was reduced on average from 14.7 weeks to 8.9 weeks with the
use of the device.
In summary, FDA's literature review resulted in findings that are
consistent with available clinical data from PMA submissions. These
studies suggest that there are probable benefits to the use of these
devices; however, differences in methodology, including differences in
devices used, treatment waveform and frequency, patient populations, as
well as anatomic location, could have had significant effects on
reported device effectiveness, which ranged from 32.8 percent to 97.4
percent. Regarding safety, the findings from these studies demonstrate
that the devices are relatively safe as the adverse event profile
associated with these devices using various modalities was similar to
controls. Overall, the studies involved 10,566 subjects (including
control subjects), with only a single report of a serious adverse event
(Biglari, Ref. 32); however, a direct link to the use of the device
could not be established for this event.
[[Page 49992]]
Further, a search of FDA's MDR database was conducted to identify
all adverse events submitted to FDA up to October 31, 2019, for devices
approved under product codes LOF and LPQ. The results of the identified
reports are consistent with the risk profiles identified in both PMA
applications and literature that were reviewed. FDA's search yielded a
total of 270 unique MDRs. The most frequently reported events were
categorized as ``skin reaction/issue'' (n = 187) followed by ``pain''
(n = 59) and ``device functional issue'' (n = 21). A review of the
adverse events regarding skin reactions found that a majority were due
to irritation from the electrode adhesive or ultrasound gel used. There
was no apparent difference in risk profile across the various device
modalities, though the risk of skin irritation was primarily observed
in the skin-contacting devices (due to the electrodes in the CC device
and the gel in the LIPUS device). For cases where followup was
described, patients recovered when treatment was discontinued. In
addition, 11 reports of ``mass/tumor'' were identified; however, the
nature of the relationship between the mass/tumor to the device was
unrelated or unclear. Based upon FDA's assessment of other systematic
reviews of these devices, no other reports of mass/tumors have been
identified (Refs. 38 to 42).
Finally, a search of FDA's Medical Device Recall database was
conducted. No recalls were found when searching the database for
devices under product code LOF. Two class 2 recalls were reported for
devices under product code LPQ; specifically, there was a recall for
the Exogen Express Bone Healing System and a recall for the Exogen
4000+ Ultrasound Bone Healing System. Both were posted on August 4,
2009, and initiated by the manufacturer because of problems with the
transducer, which may have resulted in a reduced ultrasound output.
These recalls were terminated on November 18, 2010. These recall events
reflect the risks to health identified in section V, and FDA believes
the special controls proposed, in addition to general controls, can
effectively mitigate the risks identified.
VIII. Proposed Special Controls
Table 1 outlines the risks to health identified in section V and
the corresponding mitigation measures proposed to reasonably assure
safety and effectiveness, which are discussed in more detail below.
Table 1--Risks to Health and Mitigation Measures for Non-Invasive Bone
Growth Stimulators
------------------------------------------------------------------------
Identified risk to health Mitigation measures
------------------------------------------------------------------------
Failure or delay of osteogenesis....... Clinical performance data.
Non-clinical performance
testing.
Software verification,
validation, and hazard
analysis.
Labeling.
Burn................................... Non-clinical performance
testing.
Electrical safety testing.
Labeling.
Electrical shock....................... Electrical safety testing.
Labeling.
Electromagnetic interference........... Electromagnetic compatibility
(EMC) testing.
Labeling.
Adverse tissue reaction................ Biocompatibility evaluation.
Labeling.
Adverse interaction with internal/ Labeling.
external fixation devices.
Adverse biological effects............. Non-clinical performance
testing.
Software verification,
validation, and hazard
analysis.
------------------------------------------------------------------------
The risk of failure or delay of osteogenesis is clinically
significant. To mitigate this risk, FDA proposes that manufacturers
provide clinical performance data to demonstrate that the device yields
positive outcomes (e.g., fusion of the non-union) in accordance with
its intended use. Further, FDA proposes non-clinical performance
testing to demonstrate that the device performs as intended under
anticipated conditions of use to achieve the identified successful
clinical performance characteristics. This would include verification
and validation of critical performance characteristics, including
characterization of the designed outputs of the device as well as the
outputs that are delivered to the patient, thermal safety and
reliability testing, reliability testing consistent with the expected
device use-life, and validation that signal characteristics are within
safe physiologic limits. Also, FDA proposes appropriate software
verification, validation, and hazard analysis to ensure that any device
software performs as intended. Lastly, FDA proposes labeling to provide
appropriate instructions (e.g., duration, frequency of use) to the end
user.
To mitigate the risk of skin burns, FDA proposes non-clinical
performance testing of the device to verify and validate critical
performance characteristics, demonstrate thermal safety and
reliability, validate that signal characteristics are within safe
physiologic limits, and demonstrate reliability of the device
consistent with its expected use-life. FDA also proposes electrical
safety testing to minimize the risk of thermal burns to the patient,
and specific instructions regarding proper usage and specific warnings
associated with the risk of burns.
To mitigate electrical shocks, FDA proposes electrical safety
testing to minimize the risk of shock to the patient. Furthermore, FDA
proposes labeling provisions, including instructions on appropriate
usage and maintenance, and specific warnings regarding electrical
shock.
To mitigate electromagnetic interference, FDA proposes
electromagnetic compatibility testing and labeling to minimize the risk
of adverse interaction with other electronic devices such as implanted
electronic devices.
To mitigate the risk of adverse tissue reactions, FDA proposes a
biocompatibility evaluation to ensure that the materials used in
patient-contacting components of the device are safe for skin contact
and labeling that includes warnings against use on compromised skin or
when there are known sensitivities, as well as instructions on
appropriate cleaning of any reusable components.
To mitigate the risk of adverse interaction with internal/external
fixation devices, FDA proposes labeling,
[[Page 49993]]
specifically inclusion of appropriate warnings for patients with
implanted internal/external devices.
To mitigate the risk of adverse biologic effects, FDA proposes non-
clinical performance testing to verify and validate critical
performance characteristics of the device, demonstrate thermal safety
and reliability, validate safety of the signal by reference to known
biological safety limits, and demonstrate reliability of the device
over the expected use-life. Furthermore, FDA proposes software
verification, validation, and hazard analysis.
If this reclassification is finalized, non-invasive bone growth
stimulators will be reclassified into class II and would be subject to
premarket notification (510(k)) requirements under Sec. 807.81. As
discussed below, the intent is for the reclassification to be codified
in 21 CFR 890.5870. Firms submitting a 510(k) for non-invasive bone
growth stimulators will be required to comply with the particular
mitigation measures set forth in the special controls. Adherence to the
special controls, in addition to the general controls, is necessary to
provide a reasonable assurance of the safety and effectiveness of these
devices.
IX. 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.
X. Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed order contains no new
collections of information. Therefore, clearance by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3521) is not required. This proposed order refers
to previously approved FDA collections of information. These
collections of information are subject to review by OMB under the PRA.
The collections of information in part 807, subpart E have been
approved under OMB control number 0910-0120; the collections of
information in 21 CFR part 814, subparts A through E, 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.
XI. Codification of Orders
Under section 513(f)(3) of the FD&C Act, FDA may issue final orders
to reclassify devices. 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 newly codified
orders. Therefore, under section 513(f)(3), in the proposed order, we
are proposing to codify non-invasive bone growth stimulators in the new
21 CFR 890.5870, under which non-invasive bone growth stimulators would
be reclassified from class III to class II.
XII. Proposed Effective Date
FDA proposes that any final order based on this proposal become
effective 30 days after the date of its publication in the Federal
Register.
XIII. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
1. *Guidance on Section 216 of the Food and Drug Administration
Modernization Act of 1997, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-section-216-food-and-drug-administration-modernization-act-1997-guidance-industry-and-fda.
2. *P790002 Approval available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P790002.
3. *RS Medical Corporation Reclassification Petition, available
at https://wayback.archive-it.org/7993/20170405072021/https://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4224b1-06-TabB-RSMEDICAL-Petition.pdf.
4. *FDA's Orthopaedic and Rehabilitation Devices Panel
transcript and other meeting materials for the June 2, 2006, meeting
are available at: https://wayback.archive-it.org/7993/20170403222246/https://www.fda.gov/ohrms/dockets/ac/cdrh06.html#orthopaedic.
5. *Letter from RS Medical requesting withdrawal of petition,
available at https://www.regulations.gov/document?D=FDA-2005-P-0052-0007.
6. *FDA letter granting RS Medical's withdrawal request,
available at https://www.regulations.gov/document?D=FDA-2005-P-0052-0006.
7. *First Cohort of Results of the 2014-2015 Strategic Priority:
Strike the Right Balance Between Premarket and Postmarket Data
Collection (April 2015), available at https://www.fda.gov/media/91437/download.
8. *Second and Final Cohort of Results of the 2014-2015
Strategic Priority: Strike the Right Balance Between Premarket and
Postmarket Data Collection (August 2016), available at https://www.fda.gov/media/99822/download.
9. *P030034 Summary of Safety and Effectiveness, available at
https://www.accessdata.fda.gov/cdrh_docs/pdf3/P030034B.pdf.
10. *P850022/S009 Summary of Safety and Effectiveness, available
at https://www.accessdata.fda.gov/cdrh_docs/pdf/P850022S009B.pdf.
11. *P910066/S011 Summary of Safety and Effectiveness, available
at https://www.accessdata.fda.gov/cdrh_docs/pdf/P910066S011B.pdf.
12. Yasuda, I., ``The Classic: Fundamental Aspects of Fracture
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28. Nolte, P., R. Anderson, E. Strauss, et al., ``Heal Rate of
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33. Coric, D., D.E. Bullard, V.V. Patel, et al., ``Pulsed
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34. Assiotis, A., N.P. Sachinis, and B.E. Chalidis, ``Pulsed
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36. Foley, K.T., T.E. Mroz, P.M. Arnold, et al., ``Randomized,
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37. Streit, A., B.C. Watson, J.D. Granata, et al., ``Effect on
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38. Aleem, I.S., I. Aleem, N. Evaniew, et al., ``Efficacy of
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39. Behrens, S.B., M.E. Deren, and K O. Monchik, ``A Review of
Bone Growth Stimulation for Fracture Treatment.'' Current Orthopedic
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40. Griffin, X.L., M.L. Costa, N. Parsons, et al.,
``Electromagnetic Field Stimulation for Treating Delayed Union or
Non-Union of Long Bone Fractures in Adults.'' The Cochrane Database
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41. Griffin, X.L., N. Smith, N. Parsons, et al., ``Ultrasound
and Shockwave Therapy for Acute Fractures in Adults.'' The Cochrane
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42. Hannemann, P.F., E.H.H. Mommers, J.P.M. Schots, et al.,
``The Effects of Low-Intensity Pulsed Ultrasound and Pulsed
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List of Subjects in 21 CFR Part 890
Medical 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 890 be 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, 360l, 371.
0
2. Add Sec. 890.5870 to subpart F to read as follows:
Sec. 890.5870 Non-invasive bone growth stimulator.
(a) Identification. A non-invasive bone growth stimulator provides
stimulation through electrical, magnetic, or ultrasonic fields. The
device is for prescription use and is intended to be used externally to
promote osteogenesis as an adjunct to primary treatments for fracture
fixation or spinal fusion.
(b) Classification. Class II (special controls). The special
controls for this device are:
(1) Clinical performance data must support the intended use of the
device.
(2) Non-clinical performance testing must demonstrate that the
device performs as intended under anticipated conditions of use. The
following must be provided:
(i) Verification and validation of critical performance
characteristics of the device, including characterization of the
designed outputs of the device as well as the outputs that are
delivered to the patient.
(ii) Thermal safety and thermal reliability testing.
(iii) Validation that signal characteristics are within safe
physiologic limits.
(iv) Reliability testing consistent with the expected use-life of
the device.
(3) Patient-contacting components of the device must be
demonstrated to be biocompatible.
(4) Performance data must demonstrate the electrical safety and
electromagnetic compatibility of the device.
(5) Appropriate software verification, validation, and hazard
analysis must be performed.
(6) Labeling for the device must include the following:
(i) Warning against use on compromised skin or when there are known
sensitivities;
(ii) Appropriate warnings for patients with implanted medical
devices;
(iii) A detailed summary of the clinical testing, which includes
the clinical outcomes associated with the use of the device, and a
summary of adverse events and complications that occurred with the
device;
(iv) A clear description of the device;
(v) Instructions on appropriate usage, duration, and frequency of
use;
(vi) Instructions for maintenance and safe disposal;
(vii) Instructions for appropriate cleaning of any reusable
components;
(viii) Specific warnings regarding user burns, electrical shock,
and skin irritation; and
(ix) The risks and benefits associated with use of the device.
Dated: August 4, 2020.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2020-17543 Filed 8-14-20; 8:45 am]
BILLING CODE 4164-01-P