[Federal Register Volume 79, Number 12 (Friday, January 17, 2014)]
[Rules and Regulations]
[Pages 3088-3094]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-00873]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 876 and 892
[Docket No. FDA-2013-N-0195]
Effective Date of Requirement for Premarket Approval for
Transilluminator for Breast Evaluation and Sorbent Hemoperfusion System
(SHS) Devices for the Treatment of Hepatic Coma and Metabolic
Disturbances; Reclassification of SHS Devices for the Treatment of
Poisoning and Drug Overdose
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 require the filing of a premarket approval application (PMA)
for the transilluminator for breast evaluation and sorbent
hemoperfusion system (SHS) devices for the treatment of hepatic coma
and metabolic disturbances and to reclassify SHS devices for the
treatment of poisoning and drug overdose, a preamendments class III
device, into class II (special controls).
DATES: This order is effective January 17, 2014.
FOR FURTHER INFORMATION CONTACT: Rebecca Nipper, Center for Devices and
Radiological Health, 10903 New Hampshire Ave., Bldg. 66, Rm. 1540,
Silver Spring, MD 20993, 301-796-6527.
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 of 1997 (FDAMA) (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
[[Page 3089]]
comprehensive system for the regulation of medical devices intended for
human use. Section 513 of the FD&C Act (21 U.S.C. 360c) established
three categories (classes) of devices, reflecting the regulatory
controls needed to provide reasonable assurance of their safety and
effectiveness. The three categories of devices are class I (general
controls), class II (special controls), and class III (premarket
approval).
Under section 513 of the FD&C Act, devices that were in commercial
distribution before the enactment of the 1976 amendments, May 28, 1976
(generally referred to as preamendments devices), are classified after
FDA has: (1) Received a recommendation from a device classification
panel (an FDA advisory committee); (2) published the panel's
recommendation for comment, along with a proposed regulation
classifying the device; and (3) published a final regulation
classifying the device. FDA has classified most preamendments devices
under these procedures.
Devices that were not in commercial distribution prior to May 28,
1976 (generally referred to as postamendments devices), are
automatically classified by section 513(f) of the FD&C Act into class
III without any FDA rulemaking process. Those devices remain in class
III and require premarket approval unless, and until, the device is
reclassified into class I or II or FDA issues an order finding the
device to be substantially equivalent, in accordance with section
513(i) of the FD&C Act, to a predicate device that does not require
premarket approval. The Agency determines whether new devices are
substantially equivalent to predicate devices by means of premarket
notification procedures in section 510(k) of the FD&C Act (21 U.S.C.
360(k)) and part 807 (21 CFR part 807).
A preamendments device that has been classified into class III and
devices found substantially equivalent by means of premarket
notification (510(k)) procedures to such a preamendments device or to a
device within that type (both the preamendments and substantially
equivalent devices are referred to as preamendments class III devices)
may be marketed without submission of a PMA until FDA issues a final
order under section 515(b) of the FD&C Act (21 U.S.C. 360e(b))
requiring premarket approval or until the device is subsequently
reclassified into class I or class II. Section 515(b)(1) of the FD&C
Act directs FDA to issue an order requiring premarket approval for a
preamendments class III device.
Although, under the FD&C Act, the manufacturer of class III
preamendments device may respond to the call for PMAs by filing a PMA
or a notice of completion of a product development protocol (PDP), in
practice, the option of filing a notice of completion of a PDP has not
been used. For simplicity, although corresponding requirements for PDPs
remain available to manufacturers in response to a final order under
section 515(b) of the FD&C Act, this document will refer only to the
requirement for the filing and receiving approval of a PMA.
On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA (126
Stat. 1056) amended section 513(e) of the FD&C Act, changing the
mechanism for reclassifying a device from rulemaking to an
administrative order. Section 608(b) of FDASIA amended section 515(b)
of the FD&C Act changing the mechanism for requiring premarket approval
for a preamendments class III device from rulemaking to an
administrative order. Prior to the enactment of FDASIA, FDA published
proposed rules under section 515(b) to require PMAs for the
transilluminator for breast evaluation and sorbent hemoperfusion
devices for the treatment of hepatic coma and metabolic disturbances
(75 FR 52294 at 52299, August 25, 2010; 77 FR 9610 at 9617, February
17, 2012). FDA also published a proposed rule to reclassify sorbent
hemoperfusion for the treatment of poisoning or drug overdose under
section 513(e) of the FD&C Act prior to FDASIA (77 FR 9610 at 9617).
Subsequent to the proposed rules, FDA issued a proposed
administrative order to comply with the new procedural requirements
created by FDASIA when requiring premarket approval for preamendments
class III devices or reclassifying preamendments class III devices (78
FR 20268 at 20276, April 4, 2013). Comments submitted to the
aforementioned proposed rules and proposed administrative order were
considered when developing this final order.
A. Requirement for Premarket Approval Application
FDA is requiring PMAs for the transilluminator for breast
evaluation and SHS devices when indicated for the treatment of hepatic
coma and metabolic disturbances.
Section 515(b)(1) of the FD&C Act sets forth the process for
issuing a final order. Specifically, prior to the issuance of a final
order requiring premarket approval for a preamendments class III
device, the following must occur: (1) Publication of a proposed order
in the Federal Register; (2) a meeting of a device classification panel
described in section 513(b) of the FD&C Act; and (3) consideration of
comments from all affected stakeholders, including patients, payers,
and providers. FDA published a proposed order to require PMAs for the
transilluminator for breast evaluation and sorbent hemoperfusion
devices for the treatment of hepatic coma and metabolic disturbances in
the Federal Register of April 4, 2013 (78 FR 20268 at 20276), and has
convened classification panels for the transilluminator for breast
evaluation and SHS devices when indicated for the treatment of hepatic
coma and metabolic disturbances as discussed in this document.
Section 515(b)(3) of the FD&C Act provides that FDA shall, after
the close of the comment period on the proposed order, consideration of
any comments received, and a meeting of a device classification panel
described in section 513(b) of the FD&C Act, issue a final order to
require premarket approval or publish a document terminating the
proceeding together with the reasons for such termination.
A preamendments class III device may be commercially distributed
without a PMA until 90 days after FDA issues a final order (a final
rule issued under section 515(b) of the FD&C Act prior to the enactment
of FDASIA is considered to be a final order for purposes of section
501(f) of the FD&C Act (21 U.S.C. 351(f))) requiring premarket approval
for the device, or 30 months after final classification of the device
under section 513 of the FD&C Act, whichever is later. For
transilluminator for breast evaluation and sorbent hemoperfusion
devices for the treatment of hepatic coma and metabolic disturbances,
the preamendments class III devices that are the subject of this
proposal, the later of these two time periods is the 90-day period.
Since these devices were classified in 1995 and 1983, respectively, the
30-month period has expired (60 FR 36639, July 18, 1995, and 48 FR
53012 at 53028, November 23, 1983). Therefore, section 501(f)(2)(B) of
the FD&C Act requires that a PMA for such devices be filed within 90
days of the date of issuance of this final order. If a PMA is not filed
for such devices within 90 days after the issuance of this final order,
the devices will be deemed adulterated under section 501(f) of the FD&C
Act.
Also, a preamendments device subject to the order process under
section 515(b) of the FD&C Act is not required to have an approved
investigational device exemption (IDE) (see part 812 (21
[[Page 3090]]
CFR part 812)) contemporaneous with its interstate distribution until
the date identified by FDA in the final order requiring the filing of a
PMA for the device. At that time, an IDE is required only if a PMA has
not been filed. If the manufacturer, importer, or other sponsor of the
device submits an IDE application and FDA approves it, the device may
be distributed for investigational use. If a PMA is not filed by the
later of the two dates, and the device is not distributed for
investigational use under an IDE, the device is deemed to be
adulterated within the meaning of section 501(f)(1)(A) of the FD&C Act,
and subject to seizure and condemnation under section 304 of the FD&C
Act (21 U.S.C. 334) if its distribution continues. Other enforcement
actions include, but are not limited to, the following: Shipment of
devices in interstate commerce will be subject to injunction under
section 302 of the FD&C Act (21 U.S.C. 332), and the individuals
responsible for such shipment will be subject to prosecution under
section 303 of the FD&C Act (21 U.S.C. 333). FDA requests that
manufacturers take action to prevent the further use of devices for
which no PMA has been filed.
1. Transilluminator for Breast Evaluation
On January 11, 1991, the Obstetrics and Gynecology Devices Panel
recommended that transilluminator devices for breast evaluation be
classified into class III and subject to premarket approval to provide
reasonable assurance of the safety and effectiveness of the device. The
panel concluded that there were no published studies or clinical data
demonstrating the safety and effectiveness of the device. The panel
indicated that the device presents a potential unreasonable risk of
illness or injury to the patient if the clinician relies on the device.
The panel found further that although the device's illumination level,
wavelength, and image quality can be controlled through tests and
specifications, insufficient evidence exists to determine that special
controls can be established to provide reasonable assurance of the
safety and effectiveness of the device for its intended use.
In addition, the Radiologic Devices Panel considered the
classification of the transilluminator for breast evaluation on April
12, 2012, and expressed concerns regarding the effectiveness of the
device and the potential for delayed diagnosis. The panel determined
that general controls and special controls are not sufficient to
provide a reasonable assurance of safety and effectiveness of the
device for the diagnosis of cancer, other conditions, diseases, or
abnormalities. Accordingly, the panel concluded that the device should
remain in class III. FDA agreed and continues to agree with the
recommendations of both panels and is aware of no information submitted
in response to the 515(i) Order (74 FR 16214, April 9, 2009) or
otherwise available to FDA that would support a different
classification. The Agency notes that the device has fallen into disuse
and that the published data are not adequate to demonstrate the safety
and effectiveness of the device.
FDA received and has considered two comments on this proposed
order, as well as one comment received in response to the August 25,
2010 (75 FR 52294), proposed rule as discussed in section II of this
document.
2. SHS Devices for the Treatment of Hepatic Coma and Metabolic
Disturbances
FDA held a meeting of a device classification panel described in
section 513(b) of the FD&C Act with respect to SHS devices on July 27,
2013. The panel unanimously recommended that SHS devices for the
treatment of hepatic coma and metabolic disturbances should remain in
class III (subject to premarket approval application) because there was
insufficient information to establish special controls, and that the
application of general controls is insufficient to provide a reasonable
assurance of safety and effectiveness for SHS devices that are life-
supporting and life-sustaining and, because there is no clear benefit
from the use of these devices in these vulnerable populations, there is
a potential unreasonable risk of illness or injury when used for the
treatment of hepatic coma and metabolic disturbances. The panel also
unanimously supported FDA's conclusion that the effectiveness of SHS
when indicated for the treatment of hepatic coma and metabolic
disturbances had not been established through adequate scientific
evidence. FDA published a proposed order in the Federal Register of
April 4, 2013. FDA received and has considered two comments on this
proposed order, as well as one comment received in response to the
February 17, 2012, proposed rule as discussed in section II of this
document.
B. Reclassification
FDA is reclassifying SHS devices when indicated for the treatment
of poisoning and drug overdose from class III to class II (special
controls). Section 513(e) of the FD&C Act governs reclassification of
classified preamendments devices. This section provides that FDA may,
by administrative order, reclassify a device based upon ``new
information.'' FDA can initiate a reclassification under section 513(e)
or an interested person may petition FDA to reclassify a preamendments
device. The term ``new information,'' as used in section 513(e) of the
FD&C Act, 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
520(h)(4) of the FD&C Act, added by FDAMA, provides that FDA may use,
for reclassification of a device, certain information in a PMA 6 years
after the application has been approved. 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.
Section 513(e)(1) of the FD&C Act sets forth the process for
issuing a final
[[Page 3091]]
order. 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 the public docket. FDA published a
proposed order in the Federal Register on April 4, 2013. FDA held a
meeting of a device classification panel described in section 513(b) of
the FD&C Act with respect to SHS devices on June 27, 2013 (http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/Gastroenterology-UrologyDevicesPanel/ucm358362.htm). The panel unanimously recommended
that SHS devices for the treatment of poisoning and drug overdose, a
preamendments class III device, should be reclassified into class II
because the application of general controls and special controls are
sufficient to provide reasonable assurance of safety and effectiveness
for SHS devices when intended for these uses. The panel also generally
agreed with FDA's conclusion that the available scientific evidence is
adequate to support the safety and effectiveness of SHS devices
indicated for treatment of poisoning and drug overdose, although one
member was concerned with the age of the data on which FDA's
conclusions are based. The panel further agreed that the special
controls identified by FDA were appropriate to mitigate the relevant
risks to health for this use, although there was a fairly strong
consensus for adding specificity with regard to specific elements to be
removed by this therapy and to collect further clinical data. The
identified special controls require both testing and labeling regarding
the drugs and/or poisons the device has been demonstrated to remove,
and the extent for removal/depletion of the substances. The special
controls also require that a summary of the clinical experience with
the device, including a discussion and analysis of the device safety
and performance and a list of adverse events observed during the
testing, be provided. These special controls address the panel's
recommendations.
FDA received and has considered two comments on this proposed
order, as discussed in section II of this document, as well as one
comment on the prior proposed rule (77 FR 9610).
II. Public Comments in Response to the Proposed Rule and Proposed Order
A. Transilluminator for Breast Evaluation
In response to the August 25, 2010, proposed rule (75 FR 52294 at
52299) and the April 4, 2013, proposed order to maintain the class III
classification and require the filing of a PMA for the transilluminator
for breast evaluation, FDA received three comments.
Two of the comments supported the call for PMAs for this device.
The other comment suggested the transilluminator for breast evaluation
be reclassified as a class I device. FDA disagrees. FDA convened a
meeting of the Radiological Devices Panel on April 12, 2012, as
discussed in section I of this document, which was announced in a
notice in the Federal Register on February 28, 2012 (77 FR 12064), that
considered the information provided in the comment and the suggested
class I status for this device. After considering the information
provided in the comment and other available information, the panel
determined that the device presents a potential unreasonable risk of
illness or injury and that general controls and special controls are
not sufficient to provide a reasonable assurance of safety and
effectiveness of the transilluminator for breast evaluation for the
diagnosis of cancer, other conditions, diseases, or abnormalities and
recommended the device remain in class III. FDA concurs with the
panel's recommendation.
B. SHS Devices for the Treatment of Hepatic Coma and Metabolic
Disturbances
In response to the February 17, 2012, proposed rule and the April
4, 2013, proposed order to maintain the class III classification and
require the filing of a PMA for SHS devices for the treatment of
hepatic coma and metabolic disturbances, and to reclassify sorbent
hemoperfusion devices into class II (special controls) when indicated
for the treatment of poisoning and drug overdose, FDA received three
comments.
The first comment disagreed with FDA's intent to reclassify SHS
devices for the treatment of poisoning or drug overdose to class II,
stating: ``The Food and Drug Administration's (FDA's) proposal for
these devices raises fundamental questions about whether the Center for
Devices and Radiological Health is following the law regarding the
regulation of devices that are life-sustaining or life-supporting.''
The commenter suggested that the devices proposed to be reclassified
``are high-risk devices that can cause serious injury and death, and
therefore they should remain in class III and be reviewed through the
premarket approval process for all indications.'' FDA disagrees with
this comment. According to section 513(a)(1)(C) of the FD&C Act, a
class III device is defined as a device which (1) cannot be classified
as a class I device because insufficient information exists to
determine that the application of general controls are sufficient to
provide reasonable assurance of the safety and effectiveness of the
device, and (2) cannot be classified as a class II device because
insufficient information exists to determine that the special controls
* * * would provide reasonable assurance of its safety and
effectiveness, and (3) is purported or represented to be for a use in
supporting or sustaining human life or for a use which is of
substantial importance in preventing impairment of human health, or (4)
presents a potential unreasonable risk of illness or injury. Although
FDA considers SHS devices for the treatment of poisoning and drug
overdose to be life-supporting or life-sustaining, a viewpoint which
was supported by the panel members at the June 27, 2013, device
classification panel meeting (2013 Panel), FDA believes that based on
the available evidence, special controls, in addition to general
controls, will provide a reasonable assurance of safety and
effectiveness.
FDA also believes that, while the risks to health posed by SHS
devices may be similar for its various uses, their severity in terms of
patient outcomes and mitigation strategies are different for the drug
overdose and poisoning uses, compared to the hepatic coma and metabolic
disturbances uses. This viewpoint was supported by the 2013 Panel, as
also described in section I.B. The panel provided the following
rationale for recommending that SHS devices, when indicated for drug
overdose and poisoning be reclassified to class II: (1) The special
controls listed would be effective in providing a reasonable assurance
of safety and effectiveness and (2) the risk/benefit data demonstrates
that SHS devices for drug overdose and poisoning do not pose a
potential unreasonable risk of illness or injury. Therefore, FDA
disagrees that SHS devices intended for the treatment of poisoning and
drug overdose should remain classified as class III devices.
The second commenter responded to the proposed order, reiterating
the commenter's previous comments to the 2012 proposed rule. They
stated their continued support for the requirement
[[Page 3092]]
of PMAs for SHS devices because they pose substantial risks and the
benefits of these devices are ``unknown'' and there is ``limited
scientific evidence'' regarding their effectiveness. They also
reiterated their strong opposition to the reclassification of SHS
devices for the treatment of poisoning and drug overdose. They cited
FDA's statement that ``the device may lead to the failure to remove
drugs in the treatment of poisoning or drug overdose'' as one of the
reasons for supporting their PMA recommendation and believe that it is
inappropriate to reclassify SHS devices for any indication. FDA
continues to disagree with this comment and believes that the available
scientific evidence supports the effectiveness of SHS devices for the
treatment of poisoning and drug overdose. For drug overdose and
poisoning cases, there is typically knowledge of the substance(s) which
caused the overdose or poisoning, and SHS devices can be labeled to
identify the specific substances or types of substances with which they
can be used. Since the offending substances can often be identified in
cases of poisoning or drug overdose, the SHS devices chosen to treat
these problems can be tested with the specific substances to
demonstrate their removal capabilities and the extent of removal that
may be expected. As noted previously in response to Comment 1, the 2013
Panel agreed with the FDA's conclusion of reclassification for SHS
devices when intended for drug overdose and poisoning and further
agreed that the special controls were appropriate to mitigate the risks
to health and provide a reasonable assurance of safety and
effectiveness for these patient populations.
The commenter also noted that SHS devices for the treatment of
hepatic coma and metabolic disturbances have a long list of health
risks including platelet loss, blood loss, hypotension, toxic
reactions, metabolic disturbances, and electrical shock, while there is
``no proof that the device provides clinical improvement in hepatic
coma and metabolic disturbances.'' Further, they ``strongly support
FDA's class III PMA recommendation, so that these products could not be
sold unless new data are provided that prove their safety and efficacy
for this indication.'' FDA agrees that SHS devices intended for the
treatment of hepatic coma or metabolic disturbances be kept as class
III devices for which a PMA is required to be filed. Although FDA has
identified the risks to health posed by these devices in hepatic coma
and metabolic disturbances uses, we believe we cannot adequately
identify mitigation strategies for these risks, as they apply to these
patient populations. Given the limited study of these devices and lack
of evidence of clinically meaningful effectiveness for their use in the
treatment of hepatic coma or metabolic disturbances, FDA does not
believe that there is sufficient evidence to determine that special
controls would provide reasonable assurance of safety and effectiveness
for these patient populations. The panel unanimously agreed that these
devices, when used for hepatic coma and metabolic disturbances, should
remain in class III. They also stated that it is appropriate to
maintain SHS devices for hepatic coma and metabolic disturbances in
class III because they are life-supporting and life-sustaining and,
because there is no clear benefit from the use of these devices in
these vulnerable populations, there is a potential unreasonable risk of
illness or injury.
The third commenter stated that ``Premarket approvals are necessary
to establish the safety and efficacy of [the SHS devices] and prove
that [the] possible benefits outweigh these substantial known risks.''
They ``agree with the FDA's conclusion that the safety and
effectiveness of sorbent hemoperfusion devices has not been established
by adequate scientific evidence for the treatment of hepatic coma,
because only a few randomized, controlled trials have been conducted
using this device, and these were small, poorly designed, and not
adequately powered.'' They also ``agree with the FDA that `bench
testing is not adequate in establishing the devices' safety and
effectiveness, particularly since characterizing a sorbent
hemoperfusion system's performance and adsorption capabilities has not
correlated to patient outcomes, such as resolution of the patients'
hepatic coma, or improvements in mortality.' Moreover, they note that
`there is no consensus [within the scientific literature] on the
clinical endpoints necessary to adequately evaluate sorbent
hemoperfusion devices for the treatment of hepatic coma and metabolic
disturbances or on the patient populations who will benefit the most
from the use of these devices.' '' FDA agrees with this comment
regarding the intended use of hepatic come and metabolic disturbances.
With respect to the reclassification proposal concerning SHS
devices for the treatment of poisoning and drug overdose, the commenter
stated ``The fact that quick removal of a poison or drug can generally
be expected to impact clinical outcomes does not establish that sorbent
hemoperfusion is effective in treating poisoning and drug overdose.
Several alternative mechanisms are available to remove poisons and
drugs from the body, including (1) allowing the human body to clear a
drug from the bloodstream through endogenous means (i.e. in absence of
any enhanced assistance) and (2) hemodialysis. Hemodialysis is more
effective at removing water-soluble low molecular weight compounds and
is considered preferable to hemoperfusion because it will also correct
a concurrent acid-base disturbance. It is also generally better
understood and more widely available than hemoperfusion. Hemoperfusion
treatment carries substantial risks, and death or long-term morbidity
may result due to complications from treatment. In order to assess
whether these substantial risks are outweighed by potential benefits,
the device must be compared with alternative approaches in well-
controlled clinical investigations.'' FDA disagrees with this comment
in part. While hemodialysis may be more widely used as a first line
therapy for drug overdose and poisoning, especially for water-soluble
low molecular weight compounds, not all drugs and poisons are water-
soluble. Hemoperfusion has been demonstrated to effectively remove
lipids and protein-soluble substances (e.g., barbiturates, digitalis,
carbamazepine, methotrexate, acetaminophen, and paraquat), as well as
some water-soluble substances. Sorbent hemoperfusion system devices can
be sufficiently tested on the bench for their removal capabilities
using drugs and substances typically associated with overdoses and
poisonings, and labeled to indicate which drugs or poisons are
preferentially removed by hemoperfusion and the extent of their
removal. The number of treatments required for the majority of cases of
drug overdose or poisonings would be expected to be low depending on
the degree of overdose, patient symptomatology, and the timing of the
treatment with relation to the introduction of the toxin, thus
minimizing the risks to health posed by the device. There is ample
literature to establish the safety of hemoperfusion for drug overdose
and poisoning. The published literature was presented to and discussed
with the 2013 Panel, which helped to identify the risks to health posed
by the device, and FDA believes that these known risks can be mitigated
with the special controls identified. The panel agreed with
reclassifying SHS devices for the
[[Page 3093]]
intended use of drug overdose and poisoning, and stated that FDA's list
of risks to health is comprehensive and that these risks should be
adequately mitigated by the special controls identified.
The commenter also opposed reclassification of SHS devices for drug
overdose into class II on the ground that the proposed special controls
will not adequately deter off-label use of these devices for treatment
of hepatic coma and metabolic disturbances, conditions that are far
more prevalent in the general population than accidental poisonings or
drug overdoses. They state that they ``believe that there will be
substantial financial incentives for potentially harmful off-label use
of these devices, and the proposed protections will fail to adequately
deter such use.'' FDA disagrees with this comment in that we regulate
the use of a device as indicated by the party offering the device for
interstate commerce. The intended uses for SHS devices are limited by
the codified classification.
III. The Final Order
FDA is adopting its findings as published in the preamble of the
proposed order (78 FR 20268) by issuing this final order to require the
filing of a PMA for the transilluminator for breast evaluation and SHS
devices for the treatment of hepatic coma and metabolic disturbances
under section 515(b) of the FD&C Act.
In addition, FDA is issuing this final order under section 513(e)
of the FD&C Act to reclassify SHS devices for the treatment of
poisoning and drug overdose from class III to class II and establish
special controls. This final order will revise 21 CFR part 876.
A. Transilluminator for Breast Evaluation and SHS Devices for the
Treatment of Hepatic Coma and Metabolic Disturbances
Under the final order, a PMA is required to be filed on or before
90 days after the date of publication of the final order in the Federal
Register, for any of these class III preamendments devices that were in
commercial distribution before May 28, 1976, or that has been found by
FDA to be substantially equivalent to such a device on or before 90
days after the date of publication of the final order in the Federal
Register. An approved PMA is required to be in effect for any such
devices on or before 180 days after FDA files the application. Any
other class III preamendments device subject to this order that was not
in commercial distribution before May 28, 1976, is required to have an
approved PMA in effect before it may be marketed.
If a PMA for any of the class III preamendments devices is not
filed on or before the 90th day past the effective date of this final
order, that device will be deemed adulterated under section
501(f)(1)(A) of the FD&C Act, and commercial distribution of the device
must cease immediately. The device may, however, be distributed for
investigational use, if the requirements of the IDE regulations (part
812) are met.
B. SHS Devices Intended for the Treatment of Poisoning and Drug
Overdose
Following the effective date of this final order, firms submitting
a 510(k) premarket notification for a SHS devices intended for the
treatment of poisoning and drug overdose will need either to (1) comply
with the particular mitigation measures set forth in the special
controls guideline or (2) use alternative mitigation measures, but
demonstrate to the Agency's satisfaction that those alternative
measures identified by the firm will provide at least an equivalent
assurance of safety and effectiveness.
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 sorbent hemoperfusion devices for the treatment of
poisoning and drug overdose, and therefore, this device type is not
exempt from premarket notification requirements.
An applicant whose device was legally in commercial distribution
before May 28, 1976, or whose device has been found to be substantially
equivalent to such a device, who does not intend to market such device
for the treatment of hepatic coma, and/or metabolic disturbances may
remove such intended uses from the device's labeling by initiating a
correction within 90 days after issuance of any final order based on
this proposal. Under 21 CFR 806.10(a)(2) a device manufacturer or
importer initiating a correction to remedy a violation of the FD&C Act
which may present a risk to health is required to submit a written
report of the correction to FDA.
IV. Environmental Impact
The Agency has determined under 21 CFR 25.30(h) and 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.
V. 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 812 have been approved under OMB
control number 0910-0078; 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, subpart B, have been
approved under OMB control number 0910-0231; and the collections of
information under 21 CFR part 801 have been approved under OMB control
number 0910-0485.
VI. Codification of Orders
Prior to the amendments by FDASIA, section 513(e) provided for FDA
to issue regulations to reclassify devices and section 515(b) of the
FD&C Act provided for FDA to issue regulations to require approval of
an application for premarket approval for preamendments devices or
devices found to be substantially equivalent to preamendments devices.
Sections 513(e) and 515(b) as amended require FDA to issue final orders
rather than regulations, and FDASIA provides for FDA to revoke
previously issued regulations by order. FDA will continue to codify
reclassifications and requirements for approval of an application for
premarket approval in the Code of Federal Regulations. 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 21 CFR 876.5870
related to the classification of sorbent hemoperfusion system devices
for the treatment of poisoning and drug overdose as class III devices
and codifying the reclassification of these devices into class II.
List of Subjects
21 CFR Part 876
Medical devices.
21 CFR Part 892
Medical devices, Radiation protection, X-rays.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
[[Page 3094]]
authority delegated to the Commissioner of Food and Drugs, 21 CFR parts
876 and 892 are amended as follows:
PART 876--GASTROENTEROLOGY-UROLOGY DEVICES
0
1. The authority citation for 21 CFR part 876 continues to read as
follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.
0
2. Revise Sec. 876.5870 to read as follows:
Sec. 876.5870 Sorbent hemoperfusion system.
(a) Identification. A sorbent hemoperfusion system is a
prescription device that consists of an extracorporeal blood system
similar to that identified in the hemodialysis system and accessories
(Sec. 876.5820) and a container filled with adsorbent material that
removes a wide range of substances, both toxic and normal, from blood
flowing through it. The adsorbent materials are usually activated-
carbon or resins which may be coated or immobilized to prevent fine
particles entering the patient's blood. The generic type of device may
include lines and filters specifically designed to connect the device
to the extracorporeal blood system. The device is used in the treatment
of poisoning, drug overdose, hepatic coma, or metabolic disturbances.
(b) Classification. (1) Class II (special controls) when the device
is intended for the treatment of poisoning and drug overdose. The
special controls for this device are:
(i) The device must be demonstrated to be biocompatible;
(ii) Performance data must demonstrate the mechanical integrity of
the device (e.g., tensile, flexural, and structural strength),
including testing for the possibility of leaks, ruptures, release of
particles, and/or disconnections under anticipated conditions of use;
(iii) Performance data must demonstrate device sterility and shelf
life;
(iv) Bench performance testing must demonstrate device
functionality in terms of substances, toxins, and drugs removed by the
device, and the extent that these are removed when the device is used
according to its labeling, and to validate the device's safeguards;
(v) A summary of clinical experience with the device that discusses
and analyzes device safety and performance, including a list of adverse
events observed during the testing, must be provided;
(vi) Labeling must include the following:
(A) A detailed summary of the device-related and procedure-related
complications pertinent to the use of the device;
(B) A summary of the performance data provided for the device,
including a list of the drugs and/or poisons the device has been
demonstrated to remove, and the extent for removal/depletion; and
(vii) For those devices that incorporate electrical components,
appropriate analysis and testing must be conducted to verify electrical
safety and electromagnetic compatibility of the device.
(2) Class III (premarket approval) when the device is intended for
the treatment of hepatic coma and metabolic disturbances.
(c) Date premarket approval application (PMA) or notice of
completion of product development protocol (PDP) is required. A PMA or
notice of completion of a PDP is required to be filed with FDA by April
17, 2014, for any sorbent hemoperfusion system indicated for treatment
of hepatic coma or metabolic disturbances that was in commercial
distribution before May 28, 1976, or that has, by April 17, 2014, been
found to be substantially equivalent to any sorbent hemoperfusion
device indicated for treatment of hepatic coma or metabolic
disturbances that was in commercial distribution before May 28, 1976.
Any other sorbent hemoperfusion system device indicated for treatment
of hepatic coma or metabolic disturbances shall have an approved PMA or
declared completed PDP in effect before being placed in commercial
distribution.
PART 892--RADIOLOGY DEVICES
0
3. The authority citation for 21 CFR part 892 continues to read as
follows:
Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
0
4. Revise Sec. 892.1990(c) to read as follows:
Sec. 892.1990 Transilluminator for breast evaluation.
* * * * *
(c) Date premarket approval (PMA) or notice of completion of
product development protocol (PDP) is required. A PMA or notice of
completion of a PDP is required to be filed with FDA by April 17, 2014,
for any transilluminator for breast evaluation that was in commercial
distribution before May 28, 1976, or that has, by April 17, 2014, been
found to be substantially equivalent to any transilluminator for breast
evaluation that was in commercial distribution before May 28, 1976. Any
other transilluminator for breast evaluation shall have an approved PMA
or declared completed PDP in effect before being placed in commercial
distribution.
Dated: January 13, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-00873 Filed 1-16-14; 8:45 am]
BILLING CODE 4160-01-P