Document ID: FDA-2013-N-0195-0100
Agency: fda
Document Type: Rule
Title: 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
Posted Date: 2014-01-17T05:00Z

[Federal Register Volume 79, Number 12 (Friday, January 17, 2014)]
[Rules and Regulations]
[Pages 3088-3094]
From the Federal Register Online via the Government Printing 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