Federal Register, Volume 77 Issue 33 (Friday, February 17, 2012)

[Federal Register Volume 77, Number 33 (Friday, February 17, 2012)]
[Proposed Rules]
[Pages 9610-9617]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2012-3810]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 876

[Docket No. FDA-2012-M-0076]

Gastroenterology-Urology Devices; Reclassification of Sorbent
Hemoperfusion Devices for the Treatment of Poisoning and Drug Overdose;
Effective Date of Requirement for Premarket Approval for Sorbent
Hemoperfusion Devices To Treat Hepatic Coma and Metabolic Disturbances

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to
reclassify the sorbent hemoperfusion system, a preamendments class III
device, into class II (special controls) for the treatment of poisoning
and drug overdose, and to require the filing of a premarket approval
application (PMA) or a notice of completion of a product development
protocol (PDP) for the treatment of hepatic coma and metabolic
disturbances. FDA is identifying the proposed special controls that the
Agency believes will reasonably ensure the safety and effectiveness of
the device for the treatment of poisoning and drug overdose. The Agency
is also summarizing its proposed findings regarding the degree of risk
of illness or injury designed to be eliminated or reduced by requiring
the devices to meet the statute's approval requirements and the
benefits to the public from the use of the devices. In addition, FDA is
announcing the opportunity for interested persons to request that the
Agency change the classification of any of the devices mentioned in
this document based on new information. This action implements certain
statutory requirements.

DATES: Submit either electronic or written comments by May 17, 2012.
Submit requests for a change in classification by March 5, 2012. See
section XVIII of this document for the proposed effective date of a
final rule based on this proposed rule.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2012-
M-0076, by any of the following methods:

Electronic Submissions

Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.

Written Submissions

Submit written submissions in the following ways:
Fax: 301-827-6870.
Mail/Hand delivery/Courier (for paper or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the Agency name
and Docket No. FDA-2012-M-0076 for this rulemaking. All comments
received may be posted without change to http://www.regulations.gov,
including any personal information provided. For additional information
on submitting comments, see the ``Comments'' heading of the
SUPPLEMENTARY INFORMATION section of this document.
Docket: For access to the docket to read background documents or
comments received, go to http://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 Division of
Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Melissa Burns, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, rm. 1646, Silver Spring, MD 20993, 301-796-5616,
melissa.burns@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

A. Requirement for Premarket Approval Application

The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended by
the Medical Device Amendments (the 1976 amendments) (Pub. L. 94-295),
the Safe Medical Devices Act of 1990 (SMDA) (Pub. L. 101-629), Food and
Drug Administration Modernization Act of 1997 (FDAMA) (Pub. L. 105-
115), the Medical Device User Fee and Modernization Act of 2002
(MDUFMA) (Pub. L. 107-250), the Medical Devices Technical Corrections
Act (Pub. L. 108-214), and the Food and Drug Administration Amendments
Act of 2007 (Pub. L. 110-85) establish a comprehensive system for the
regulation of medical devices intended for human use. Section 513 of
the FD&C Act (21 U.S.C. 360c) established three categories (classes) of
devices, reflecting the regulatory controls needed to provide
reasonable assurance of their safety and effectiveness. The three
categories of devices are class I (general controls), class II (special
controls), and class III (premarket approval).
Under section 513 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 21 CFR part 807.
A preamendments device that has been classified into class III may
be

[[Page 9611]]

marketed by means of premarket notification procedures (510(k) process)
without submission of a PMA until FDA issues a final regulation under
section 515(b) of the FD&C Act (21 U.S.C. 360e(b)) requiring premarket
approval. Section 515(b)(1) of the FD&C Act establishes the requirement
that a preamendments device that FDA has classified into class III is
subject to premarket approval. A preamendments class III device may be
commercially distributed without an approved PMA or a notice of
completion of a PDP until 90 days after FDA issues a final rule
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. Also, a preamendments device subject to the
rulemaking procedure under section 515(b) of the FD&C Act is not
required to have an approved investigational device exemption (IDE)
(see part 812 (21 CFR part 812)) contemporaneous with its interstate
distribution until the date identified by FDA in the final rule
requiring the submission of a PMA for the device. At that time, an IDE
is required only if a PMA has not been submitted or a PDP completed.
Section 515(b)(2)(A) of the FD&C Act provides that a proceeding to
issue a final rule to require premarket approval shall be initiated by
publication of a notice of proposed rulemaking containing: (1) The
regulation; (2) proposed findings with respect to the degree of risk of
illness or injury designed to be eliminated or reduced by requiring the
device to have an approved PMA or a declared completed PDP and the
benefit to the public from the use of the device; (3) an opportunity
for the submission of comments on the proposed rule and the proposed
findings; and (4) an opportunity to request a change in the
classification of the device based on new information relevant to the
classification of the device.
Section 515(b)(2)(B) of the FD&C Act provides that if FDA receives
a request for a change in the classification of the device within 15
days of the publication of the notice, FDA shall, within 60 days of the
publication of the notice, consult with the appropriate FDA advisory
committee and publish a notice denying the request for change in
reclassification or announcing its intent to initiate a proceeding to
reclassify the device under section 513(e) of the FD&C Act. Section
515(b)(3) of the FD&C Act provides that FDA shall, after the close of
the comment period on the proposed rule and consideration of any
comments received, issue a final rule to require premarket approval or
publish a document terminating the proceeding together with the reasons
for such termination. If FDA terminates the proceeding, FDA is required
to initiate reclassification of the device under section 513(e) of the
FD&C Act, unless the reason for termination is that the device is a
banned device under section 516 of the FD&C Act (21 U.S.C. 360f).
If a proposed rule to require premarket approval for a
preamendments device is finalized, section 501(f)(2)(B) of the FD&C Act
(21 U.S.C. 351(f)(2)(B)) requires that a PMA or notice of completion of
a PDP for any such device be filed within 90 days of the date of
issuance of the final rule or 30 months after the final classification
of the device under section 513 of the FD&C Act, whichever is later. If
a PMA or notice of completion of a PDP is not filed by the later of the
two dates, commercial distribution of the device is required to cease
since the device would be deemed adulterated under section 501(f) of
the FD&C Act.
The device may, however, be distributed for investigational use if
the manufacturer, importer, or other sponsor of the device complies
with the IDE regulations. If a PMA or notice of completion of a PDP is
not filed by the later of the two dates, and the device does not comply
with IDE regulations, 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. 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). In the past, FDA has requested that manufacturers take action to
prevent the further use of devices for which no PMA or PDP has been
filed and may determine that such a request is appropriate for the
class III devices that are the subjects of this regulation.
The FD&C Act does not permit an extension of the 90-day period
after issuance of a final rule within which an application or a notice
is required to be filed. The House Report on the 1976 amendments states
that ``[t]he thirty month grace period afforded after classification of
a device into class III * * * is sufficient time for manufacturers and
importers to develop the data and conduct the investigations necessary
to support an application for premarket approval (H. Rept. 94-853, 94th
Cong., 2d sess. 42 (1976)).''
The SMDA added section 515(i) to the FD&C Act requiring FDA to
review the classification of preamendments class III devices for which
no final rule requiring the submission of PMAs has been issued and to
determine whether or not each device should be reclassified into class
I or class II or remain in class III. For devices remaining in class
III, the SMDA directed FDA to develop a schedule for issuing
regulations to require premarket approval. The SMDA does not, however,
prevent FDA from proceeding immediately to rulemaking under section
515(b) of the FD&C Act on specific devices, in the interest of public
health, independent of the procedures of section 515(i). Proceeding
directly to rulemaking under section 515(b) of the FD&C Act is
consistent with Congress' objective in enacting section 515(i), i.e.,
that preamendments class III devices for which PMAs have not been
previously required either be reclassified to class I or class II or be
subject to the requirements of premarket approval. Moreover, in this
proposed rule, interested persons are being offered the opportunity to
request reclassification of any of the devices.

B. Reclassification

Section 513(e) of the FD&C Act governs reclassification of
classified preamendments devices. This section provides that FDA may,
by rulemaking, reclassify a device (in a proceeding that parallels the
initial classification proceeding) 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 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 regulatory action where the
reevaluation is made in light of newly available regulatory authority
(see Bell v. Goddard, supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762
F. Supp. 382, 388-389 (D.D.C. 1991)) or in light of changes in
``medical science.'' (See Upjohn v. Finch, supra, 422 F.2d at 951.).
Whether data before the Agency are past or new data, the ``new

[[Page 9612]]

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 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.), cert. denied, 474 U.S. 1062
(1985).)
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 secrets 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.
FDAMA added a new section 510(m) to the FD&C Act. New 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 assure the safety and effectiveness of the device.

II. Regulatory History of the Device

In the preamble to the proposed rule (46 FR 7562, January 23, 1981,
and 46 FR 7630, January 23, 1981), the Gastroenterology-Urology Device
Classification Panel (the Panel) recommended that sorbent hemoperfusion
systems be classified into class III because the device is life
sustaining and life supporting and because there was a lack of data on
the absorption characteristics of this device regarding the possibility
that it may, while removing toxic substances, also remove essential
substances from the blood or cause loss or platelets and white cells.
The Panel indicated that general controls alone would not be sufficient
and that there was not enough information to establish a performance
standard. Consequently, the Panel believed that premarket approval was
necessary to assure the safety and effectiveness of the device. In
1983, FDA classified sorbent hemoperfusion systems into class III after
receiving no comments on the proposed rule (48 FR 53012, November 23,
1983). In 1987, FDA published a clarification by inserting language in
the codified language stating that no effective date had been
established for the requirement for premarket approval for sorbent
hemoperfusion system devices (52 FR 17732 at 17738, May 11, 1987).
In 2009, FDA published an order for the submission of information
on sorbent hemoperfusion systems by August 7, 2009 (74 FR 16214, April
9, 2009). In response to that order, FDA received one reclassification
petition from a device manufacturer recommending that sorbent
hemoperfusion systems be reclassified to class II. The manufacturers
stated that safety and effectiveness of these devices may be assured by
device design, performance testing, and labeling (special controls).

III. Device Description

A sorbent hemoperfusion system is a device that consists of an
extracorporeal blood system 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. Sorbent
hemoperfusion systems may also include the machine or instrument used
to drive and manage blood and fluid flow within the extracorporeal
circuit, as well as any accompanying controllers, monitors, or sensors.

IV. Proposed Reclassification

FDA is proposing that sorbent hemoperfusion systems intended for
the treatment of poisoning and drug overdose be reclassified from class
III to class II. FDA believes that the identified special controls
would provide reasonable assurance of safety and effectiveness.
Therefore, in accordance with sections 513(e) and 515(i) of the FD&C
Act and Sec. 860.130 (21 CFR 860.130), based on new information with
respect to the devices, FDA, on its own initiative, is proposing to
reclassify this preamendments class III device intended for the
treatment of poisoning and drug overdose into class II. The Agency has
identified special controls that would provide reasonable assurance of
their safety and effectiveness. The Agency does not intend to exempt
this proposed class II device from premarket notification (510(k))
submission as provided for under section 510(m) of the FD&C Act.

V. Risks to Health

After considering the information from the reports and
recommendations of the advisory committees (panels) for the
classification of these devices along with information submitted in
response to the 515(i) order and any additional information that FDA
has encountered, FDA has evaluated the risks to health associated with
the use of sorbent hemoperfusion systems and determined that the
following risks to health are associated with its use:
Extracorporeal leaks (blood loss)--Rupture of the
extracorporeal circuit, cartridge, filters, and/or tubing, as well as
disconnections, may lead to blood leaks and blood loss.
Platelet loss and thrombocytopenia--The adsorption
characteristics of the device may cause large losses of platelets
during hemoperfusion.
Leukopenia--The materials used, or the design of the
device, may cause absorption of leukocytes, leading to the transient
loss of leukocytes in a patient.
Hemolysis--The materials used, or the design of the blood
pathways in the device, may cause the lysis of red blood cells.
Leak of adsorbent agent into fluid path (release of
emboli)--Fine particles leached from the sorbent column of the device
may be deposited in the arterioles of the lungs and other organ as
particulate emboli.
Lack of sterility--Improper sterilization or compromise of
the device packaging may lead to the introduction of microorganisms,
which may be transmitted to a patient during use.
Toxic and/or pyrogenic reactions--Toxic substances may be
leached from the device, causing a patient to have a pyrogenic reaction
(sudden fever with collapse and chills).
Infection--Defects in the design or construction of the
device preventing adequate cleaning and/or sterilization may allow
pathogenic organisms to be introduced and may cause an infection in a
patient.
Hypotension--Sudden fluid shifts within the patient, due
to pressures exerted by the device, or to fluid being removed by the
device, may cause sudden decreases in a patient's blood pressure.
Lack of biocompatibility in materials or solutions
contacting blood--The patient-contacting materials of the device may
cause an adverse

[[Page 9613]]

immunological or allergic reaction in a patient.
Clotting (blood loss)--The materials used, or the design
of the device, may cause a patient's blood to form clots, which may
obstruct the device's extracorporeal circuit, interrupting or
terminating treatments, and also leading to blood loss, because the
blood entrapped in the clotted blood circuit often cannot be returned
to the patient.
Removal or depletion of vital nutrients, hormones,
vitamins, substances. and drugs (e.g., adsorption of glucose,
unspecific removal characteristics, drop in patients' hematocrit), due
to device's lack of specificity--The adsorption characteristics of the
device may cause removal or depletions of nutrients, hormones, and
other necessary substances.
Metabolic disturbances--The removal of normal metabolites
along with undesirable substances may lead to metabolic disturbances.
Lack of effectiveness--The adsorption characteristics of
the device may lead to the failure to remove drugs in the treatment of
poisoning or drug overdose, or to bring on clinical improvement in
hepatic coma and metabolic disturbances.
Treatment interruptions or discontinuations--Inadequate
safeguards in the device may lead to treatment interruptions or
discontinuations in the case of power failures.
Electrical shock due to lack of electrical safety--
Inadequate safeguards in the device may lead to electrical shocks in
patients using them.
Electromagnetic interference, which may lead to adverse
interactions with other patient systems--Inadequate safeguards in the
device may lead to its interference with other patient systems, causing
adverse events in the patient, as well as adversely affecting the
performance of the other patient systems.

VI. Summary of Reasons for Reclassification

FDA believes that sorbent hemoperfusion systems intended for the
treatment of poisoning and drug overdose should be reclassified into
class II because special controls, in addition to general controls, can
be established to provide reasonable assurance of the safety and
effectiveness of the device. In addition, there is now adequate
effectiveness information sufficient to establish special controls to
provide such assurance.

VII. Summary of Data Upon Which the Reclassification Is Based

Since the time of the original Panel recommendation, sufficient
evidence has been developed to support a reclassification of sorbent
hemoperfusion system to class II with special controls for the
treatment of poisoning and hepatic coma. Evidence including reports of
clinical evaluations and case studies of the use of these devices in
the treatment of poisoning and drug overdose, and bench studies in
which the devices' abilities to remove certain drugs have been well
characterized.

VIII. Proposed Special Controls

FDA believes that the following special controls are sufficient to
mitigate the risks to health described in section IV in this document
for the treatment of poisoning and drug overdose:
The device should be demonstrated to be biocompatible;
Performance data to 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;
Performance data to demonstrate device sterility and shelf
life;
Bench performance data to 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;
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;
Labeling controls, including appropriate warnings,
precautions, cautions, and contraindications statements to alert and
inform users of proper device use and potential clinical adverse
effects, including blood loss, platelet loss, leukopenia, hemolysis,
hypotension, clotting, metabolic disturbances, and loss of vital
nutrients and substances. Labeling recommendations must be consistent
with the performance data obtained for the device, and must include a
list of the drugs the device has been demonstrated to remove, and the
extent of removal/depletion; and
For those devices that incorporate electrical components,
appropriate analysis and testing to validate electrical safety and
electromagnetic compatibility.

IX. Dates New Requirements Apply

In accordance with section 515(b) of the FD&C Act, FDA is proposing
to require that a PMA or a notice of completion of a PDP be filed with
the Agency for class III devices within 90 days after issuance of any
final rule based on this proposal. 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, will be
permitted to continue marketing such class III devices during FDA's
review of the PMA or notice of completion of the PDP. FDA intends to
review any PMA for the device within 180 days and any notice of
completion of a PDP for the device within 90 days of the date of
filing. FDA cautions that under section 515(d)(1)(B)(i) of the FD&C
Act, the Agency may not enter into an agreement to extend the review
period for a PMA beyond 180 days unless the Agency finds that ``the
continued availability of the device is necessary for the public
health.''
FDA intends that under Sec. 812.2(d), the preamble to any final
rule based on this proposal will state that, as of the date on which
the filing of a PMA or a notice of completion of a PDP is required to
be filed, the exemptions from the requirements of the IDE regulations
for preamendments class III devices in Sec. 812.2(c)(1) and (c)(2)
will cease to apply to any device that is: (1) Not legally on the
market on or before that date or (2) legally on the market on or before
that date but for which a PMA or notice of completion of a PDP is not
filed by that date, or for which PMA approval has been denied or
withdrawn.
If a PMA or notice of completion of a PDP for a class III device is
not filed with FDA within 90 days after the date of issuance of any
final rule requiring premarket approval for the device, commercial
distribution of the device must cease. The device may be distributed
for investigational use only if the requirements of the IDE regulations
are met. The requirements for significant risk devices include
submitting an IDE application to FDA for its review and approval. An
approved IDE is required to be in effect before an investigation of the
device may be initiated or continued under Sec. 812.30. FDA,
therefore, cautions that IDE applications should be submitted to FDA at
least 30 days before the end of the 90-day period after the issuance of
the final rule to avoid interrupting investigations.

X. Proposed Findings With Respect to Risks and Benefits

As required by section 515(b) of the FD&C Act, FDA is publishing
its proposed findings regarding: (1) The degree of risk of illness or
injury

[[Page 9614]]

designed to be eliminated or reduced by requiring that this device have
an approved PMA or a declared completed PDP when indicated for the
treatment of hepatic coma and metabolic disturbances and (2) the
benefits to the public from the use of the sorbent hemoperfusion system
for treatment of hepatic coma and metabolic disturbances.
These findings are based on the reports and recommendations of the
advisory committees (panels) for the classification of these devices
along with information submitted in response to the 515(i) Order, (74
FR 16214) and any additional information that FDA has encountered.
Additional information regarding the risks as well as classification
associated with this device type can be found in 46 FR 7630, 46 FR
7562, and 48 FR 53023.
For the treatment of hepatic coma and metabolic disturbances, FDA
concludes that the safety and effectiveness of these devices have not
been established by adequate scientific evidence, and the Agency
continues to agree with the Panel's recommendation. The review of the
published scientific literature revealed mostly observational studies
performed with sorbent hemoperfusion devices. Only a few randomized,
controlled trials were found, but sample sizes were small and not
adequately powered, and etiologies and control group criteria were
varied. Furthermore, based on FDA's experience reviewing these devices
for use in the treatment of hepatic coma and metabolic disturbances,
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. The scientific literature
also revealed that there is no consensus 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.

XI. PMA Requirements

A PMA for sorbent hemoperfusion system indicated for the treatment
of hepatic coma and metabolic disturbances must include the information
required by section 515(c)(1) of the FD&C Act. Such a PMA should also
include a detailed discussion of the risks identified previously, as
well as a discussion of the effectiveness of the device for which
premarket approval is sought. In addition, a PMA must include all data
and information on: (1) Any risks known, or that should be reasonably
known, to the applicant that have not been identified in this document;
(2) the effectiveness of the device that is the subject of the
application; and (3) full reports of all preclinical and clinical
information from investigations on the safety and effectiveness of the
device for which premarket approval is sought.
A PMA must include valid scientific evidence to demonstrate
reasonable assurance of the safety and effectiveness of the device for
its intended use (see Sec. 860.7(c)(2)). Valid scientific evidence is
``evidence from well-controlled investigations, partially controlled
studies, studies and objective trials without matched controls, well-
documented case histories conducted by qualified experts, and reports
of significant human experience with a marketed device, from which it
can fairly and responsibly be concluded by qualified experts that there
is reasonable assurance of the safety and effectiveness of a device
under its conditions of use. * * * Isolated case reports, random
experience, reports lacking sufficient details to permit scientific
evaluation, and unsubstantiated opinions are not regarded as valid
scientific evidence to show safety or effectiveness. * * *'' (Sec.
860.7(c)(2)).

XII. PDP Requirements

A PDP for sorbent hemoperfusion system indicated for the treatment
of hepatic coma and metabolic disturbances may be submitted in lieu of
a PMA and must follow the procedures outlined in section 515(f) of the
FD&C Act. A PDP must provide: (1) A description of the device, (2)
preclinical trial information (if any), (3) clinical trial information
(if any), (4) a description of the manufacturing and processing of the
devices, (5) the labeling of the device, and (6) all other relevant
information about the device. In addition, the PDP must include
progress reports and records of the trials conducted under the protocol
on the safety and effectiveness of the device for which the completed
PDP is sought.

XIII. Opportunity To Request a Change in Classification

Before requiring the filing of a PMA or notice of completion of a
PDP for a device, FDA is required by section 515(b)(2)(A)(i) through
(b)(2)(A)(iv) of the FD&C Act and Sec. 860.132 to provide an
opportunity for interested persons to request a change in the
classification of the device based on new information relevant to the
classification. Any proceeding to reclassify the device will be under
the authority of section 513(e) of the FD&C Act.
A request for a change in the classification of these devices is to
be in the form of a reclassification petition containing the
information required by Sec. 860.123 (21 CFR 860.123), including new
information relevant to the classification of the device.
The Agency advises that to ensure timely filing of any such
petition, any request should be submitted to the Division of Dockets
Management (see ADDRESSES) and not to the address provided in Sec.
860.123(b)(1). If a timely request for a change in the classification
of these devices is submitted, the Agency will, within 180 days after
receipt of the petition, and after consultation with the appropriate
FDA resources, publish an order in the Federal Register that either
denies the request or gives notice of its intent to initiate a change
in the classification of the device in accordance with section 513(e)
of the FD&C Act and Sec. 860.130 of the regulations.

XIV. Environmental Impact

The Agency has determined under 21 CFR 25.30(h) 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.

XV. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct Agencies to assess all
costs and benefits of available regulatory alternatives and, when
regulation is necessary, to select regulatory approaches that maximize
net benefits (including potential economic, environmental, public
health and safety, and other advantages; distributive impacts; and
equity). The Agency believes that this proposed rule is not a
significant regulatory action defined by Executive Order 12866.
The Regulatory Flexibility Act requires Agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. The Agency proposes to certify that the final rule
will not have a significant economic impact on a substantial number of
small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires

[[Page 9615]]

that Agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $136 million, using the most current (2010) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount.

A. Objective of the Proposed Rule

The objective of this proposed rule is to classify sorbent
hemoperfusion devices, which are preamendments class III devices. These
devices are used in the treatment of drug overdose, poisoning, hepatic
coma, and metabolic disturbances. The classification of these devices
will be split into two parts based on the indication of use. Devices
indicated for treatment of poisoning and drug overdose will be
reclassified into class II with special controls. Devices indicated for
treatment in hepatic coma and metabolic disturbances will be maintained
in class III with PMA or PDP requirements. Sorbent hemoperfusion
systems were originally classified as class III because they are life
sustaining and life supporting, and there was lack of data to establish
an adequate performance standard for these devices. Since that time,
sufficient evidence has been accumulated to develop special controls
for the treatment of poisoning and drug overdose, and the risks to
health are now well characterized and understood. However, there is
insufficient scientific evidence to develop special controls for these
devices when used for the treatment of hepatic coma and metabolic
disturbances. The call for PMAs or PDPs will allow for adequate
evaluation of the device, particularly with respect to the clinical
data necessary to support the safety and effectiveness of these devices
when used in the treatment of these conditions.

B. Sorbent Hemoperfusion Systems for the Treatment of Poisoning and
Drug Overdose

This rule proposes to reclassify sorbent hemoperfusion devices for
the treatment of drug overdose and poisoning into class II devices with
special controls. Currently, manufacturers of sorbent hemoperfusion
devices are subject to premarket notification requirements similar to
most class II devices, with manufacturers receiving clearance to market
via a 510(k) premarket notification submission with no premarket
approval (PMA) requirement. FDA has concluded that special controls are
sufficient for ensuring the safety and effectiveness of these devices
and that these devices may be reclassified to class II (special
controls).
FDA's Premarket Notification 510(k) database identifies five
manufacturers of six sorbent hemoperfusion devices. All six of these
devices have been cleared for use in the treatment of drug overdose and
poisoning. According to the 2005-2009 annual reports of the American
Association of Poison Control Centers' National Poison Data Systems,
hemoperfusion was used in an average of 27 cases per year, which
suggests limited use of this device for these indications.
The proposed rule would require that manufacturers who wish to
market new sorbent hemoperfusion devices or implement changes to
existing marketed devices indicated for the treatment of poisoning and
drug overdose submit 510(k)s that comply with the proposed special
controls. As current practice, the Agency already recommends that
manufacturers adopt the risk mitigations that are being proposed as
special controls, so this rule would essentially formalize current
practice as a regulation for these devices. Hence, this
reclassification will not result in any significant changes in how
510(k)s for the affected devices are prepared or in how they are
reviewed, and compliance with the special controls proposed for this
device will not yield significant new costs for affected manufacturers.
Because the formal reclassification of the affected devices from class
III to class II with special controls is consistent with current FDA
and industry practice, the Agency concludes that the proposed rule
would impose no additional regulatory burdens on the manufacturing and
marketing of sorbent hemoperfusion devices for the treatment of drug
overdose and poisoning.

C. Sorbent Hemoperfusion Systems for the Indications of Hepatic Coma
and Metabolic Disturbances

1. Benefits
The proposed requirement for PMAs or PDPs for sorbent hemoperfusion
systems for treatment of hepatic coma and metabolic disturbances would
generate social benefits equal to the value of information generated by
the safety and effectiveness tests that producers of the device would
be required to conduct under the proposed call for PMAs or PDPs.
Provided first to FDA, this information would assist physicians,
patients, and insurance providers to make more informed decisions
regarding the safe and proper use of these devices, which would also be
expected to improve some patient outcomes. There are currently no
actively marketed products that are cleared for the indication of
hepatic coma and metabolic disturbances. However, FDA projects that two
firms are likely to enter the market in the near future.
Hepatic coma is characterized as the final state of hepatic
encephalopathy, a complication of liver failure in which the brain
function progressively deteriorates. Hepatic encephalopathy is a
condition in which toxic substances that are normally cleared from the
body by the liver accumulate in the blood, eventually traveling to the
brain. Hepatic coma marks the final stage of encephalopathy, at which
the disturbance of the brain function leads to loss of consciousness.
Sorbent hemoperfusion systems can be used as a treatment device to
compensate for liver failure by removing toxins from the blood.
Data from the Healthcare Cost and Utilization Project, a nationally
representative sample of hospital discharges, suggest that hepatic coma
related hospitalizations are associated with prolonged and costly
hospital stays. In 2009, there were approximately 43,500 patients
hospitalized in the United States for a primary diagnosis of hepatic
coma. The number of discharges rises to over 115,000 when accounting
for all-listed diagnoses, which include all diagnoses that coexist at
the time of admission or that develop during hospitalization. For
patients admitted with a primary diagnosis of hepatic coma, the mean
length of stay was 5.8 days, with a mean cost of $10,000 per stay. In-
hospital mortality was nearly 8 percent in 2009, while the survival
rate after 3 years among patients with hepatic encephalopathy is
estimated to be 25 percent (Ref. 1).
There is limited scientific evidence regarding the effectiveness of
sorbent hemoperfusion systems for the indication of hepatic coma, which
could partially be due to the fragile nature of the patient population
(i.e., individuals who are acutely ill due to liver disease, and thus
face poor clinical prognosis and high mortality). Because the risks and
benefits of these devices for this indication are unknown and therefore
cannot be adequately characterized, it is impossible to estimate the
direct effect of the devices on patient outcomes. However, if they are
approved, the

[[Page 9616]]

devices have the potential to greatly improve patient outcomes relative
to the current baseline, since there are no alternative devices
currently on the market. The PMA requirement will provide clinical
testing to establish the safety and efficacy of the devices, to
characterize their performance, and to determine the patient
populations who will benefit most from the use of these devices.
Clinical trials may also identify design issues that would have gone
unnoticed in a premarket notification process, thereby reducing the
potential of device failures. Furthermore, PMA requirements allow for
continuing postmarketing evaluation and periodic reporting to FDA on
the safety, effectiveness, and reliability of the device for its
intended use.
2. Costs
The proposed rule would require producers of sorbent hemoperfusion
for treatment of hepatic coma and metabolic disturbances to obtain a
PMA or PDP prior to marketing new products. Currently, producers of
sorbent hemoperfusion systems receive clearance to market these devices
through the less costly 510(k) premarket notification process. The
incremental cost of this rule for those who are developing devices to
treat hepatic coma and metabolic disturbance would be the difference
between the cost of preparing and submitting a premarket approval
application and the cost of preparing and submitting a 510(k)
application. The cost of preparing an average 510(k) application has
been estimated to be $21 per page, or $37 after adjusting for inflation
(Ref. 2). According to FDA industry experts, the number of pages in
510(k) submissions can range from an average of 400 for simple devices
to 4,000 pages for more complicated systems. Assuming that the devices
for this indication of treatment are complex in nature due to the
intricate health conditions of the intended patient population, we use
4,000 pages as our primary estimate. At a cost per page of $37, this
yields an average cost of preparing and submitting a 510(k) of
$148,000. FDA has estimated an upper bound on the cost of preparing and
submitting a PMA at approximately $1,000,000 (see, for example, 73 FR
7498 at 7502, February 8, 2008), which rises to $1,019,000 after
inflation. This yields a difference of $871,000 between the costs of
PMA and 510(k) preparation. Manufacturers must also pay FDA user fees.
For fiscal year 2012, the user fee for a 510(k) submission is $4,049
for large firms and $2,024 for small firms (76 FR 45826 at 45828,
August 1, 2011). The user fee for a premarket application (PMA or PDP)
is currently set at $220,050 for large firms and $55,013 for small
firms (76 FR 45828). This yields a cost difference of PMA and 510(k)
submission costs of $216,001 for large companies and $52,989 for small
businesses. The total incremental upfront rule-induced cost to industry
of preparing and submitting a PMA or PDP is $1,083,950 for large firms
and $908,901 for small firms. Manufacturers also incur postmarketing
annual fees for periodic reporting to FDA, with the standard fee for
annual reports currently set at $7,702 for large firms and $1,925 for
small firms.
In addition to the cost to industry of preparing and submitting
PMAs or PDPs, the proposed rule would impose review costs on FDA. It
has been estimated that, for devices reviewed by FDA's Center for
Devices and Radiological Health in 2003 and 2004, review costs were
$563,000 per PMA and $13,400 per 510(k) (Ref. 3). Updated for inflation
to 2010 dollars, these review costs become $653,000 per PMA and $15,500
per 510(k). This yields an incremental cost to FDA of $637,500. A
portion of this total will be paid by industry in the form of user
fees, with the remainder borne by general revenues.
The social costs per PMA would be the sum of the difference between
a PMA and a 510(k) and the additional FDA costs of reviewing the PMA,
or $1,508,500 (= $871,000 + $637,500). The annual cost of the proposed
rule would be the number of submissions multiplied by the cost per
submission. Because we project that few entities will introduce this
device, the number of submissions in most years will be zero. FDA
requests comments on the methods and results of our estimation.

D. Impact on Small Entities

The Regulatory Flexibility Act requires Agencies to prepare an
initial regulatory analysis if a proposed rule would have a significant
effect on a substantial number of small businesses, nonprofit
organizations, local jurisdictions, or other entities. The proposed
rule will yield no new costs for the five producers of sorbent
hemoperfusion devices for the treatment of drug overdose and poisoning,
as the rule is essentially a formalization of current industry
practice. There are currently no companies actively participating in
the market for the indications of hepatic coma and metabolic
disturbance, which will require PMAs or PDPs as a result of the
proposed rule. FDA projects that very few entities will enter this
market in the near future. If a small entity were to enter the market,
the reduced user fees would provide some relief. FDA requests comments
on the overall effect of the proposed classification on the potential
entry of small entities.
Because this proposed rule would impose no additional regulatory
burdens for manufacturers of sorbent hemoperfusion devices currently in
the market and there is limited participation in the market for devices
that will require PMAs or PDPs, FDA concludes that this proposed rule
would not have a significant economic impact on a substantial number of
small entities.

XVI. Federalism

FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. FDA has determined that
the proposed rule, if finalized, would not contain policies that would
have substantial direct effects on the States, on the relationship
between the National Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
Accordingly, the Agency tentatively concludes that the proposed rule
does not contain policies that have federalism implications as defined
in the Executive order and, consequently, a federalism summary impact
statement is not required.

XVII. Paperwork Reduction Act of 1995

This proposed rule 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 21 CFR part 812 have been approved under
OMB control number 0910-0078; the collections of information in 21 CFR
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.

XVIII. Proposed Effective Date

FDA is proposing that any final rule based on this proposal become
effective on the date of its publication in the Federal Register or at
a later date if stated in the final rule.

XIX. Comments

Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written

[[Page 9617]]

comments regarding this document. It is only necessary to submit one
set of comments. Identify comments with the docket number found in the
brackets in the heading of this document. Received comments may be seen
in the Division of Dockets Management between 9 a.m. and 4 p.m., Monday
through Friday.

XX. References

The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen by
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
(FDA has verified the Web site address, but FDA is not responsible for
any subsequent changes to the Web site after this document publishes in
the Federal Register.)

1. Schiano, T.D., ``Clinical Management of Hepatic Encephalopathy,''
vol. 30, pp. 10S-15S, Pharmacotherapy, 2010.
2. Blozan, C.F. and S.A. Tucker, ``Premarket Notifications: The
First 24,000,'' pp. 59-69, Medical Device & Diagnostic Industry,
1986.
3. Geiger, D.R., ``FY 2003 and FY 2004 Unit Costs for the Process of
Medical Device Review,'' (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/Overview/MedicalDeviceUserFeeandModernizationActMDUFMA/ucm109216.pdf),
September 2005.

List of Subjects in 21 CFR Part 876

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 876 be amended as follows:

PART 876--GASTROENTEROLOGY-UROLOGY DEVICES

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.

2. Section 876.5870 is amended by revising paragraphs (b) and (c)
to read as follows:

Sec. 876.5870 Sorbent hemoperfusion system.

* * * * *
(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 should be demonstrated to be biocompatible;
(ii) Performance data to 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;
(iii) Performance data to demonstrate device sterility and shelf
life;
(iv) Bench performance data to 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;
(v) 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;
(vi) Labeling controls, including appropriate warnings,
precautions, cautions, and contraindications statements to alert and
inform users of proper device use and potential clinical adverse
effects, including blood loss, platelet loss, leukopenia, hemolysis,
hypotension, clotting, metabolic disturbances, and loss of vital
nutrients and substances; Labeling recommendations must be consistent
with the performance data obtained for the device, and must include a
list of the drugs 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 to validate electrical safety and
electromagnetic compatibility.
(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 on or
before [date 90 days after date of publication of the final rule in the
Federal Register], 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, on or before
[date 90 days after date of publication of the final rule in the
Federal Register], 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.

Dated: February 14, 2012.
Nancy K. Stade,
Deputy Director for Policy, Center for Devices and Radiological Health.
[FR Doc. 2012-3810 Filed 2-16-12; 8:45 am]
BILLING CODE 4160-01-P