Federal Register, Volume 78 Issue 5 (Tuesday, January 8, 2013)

[Federal Register Volume 78, Number 5 (Tuesday, January 8, 2013)]
[Proposed Rules]
[Pages 1158-1162]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2013-00086]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 868 and 870

[Docket No. FDA-2012-N-1174]

Anesthesiology Devices; Reclassification of Membrane Lung for
Long-Term Pulmonary Support; Redesignation as Extracorporeal Circuit
and Accessories for Long-Term Pulmonary/Cardiac Support

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: On its own initiative, based on new information, the Food and
Drug Administration (FDA) is proposing to reclassify membrane lung
devices for long-term pulmonary support, a preamendments class III
device, into class II (special controls) for conditions where imminent
death is threatened by cardiopulmonary failure in neonates and infants
or where cardiopulmonary failure results in the inability to separate
from cardiopulmonary bypass following cardiac surgery. A membrane lung
for long-term pulmonary support refers to the oxygenator component of
an extracorporeal circuit used during long-term procedures, commonly
referred to as extracorporeal membrane oxygenation (ECMO). Because
circuit components used with the oxygenator are to be subject to the
same regulatory controls, all of the device components used in an ECMO
procedure are being considered in the scope of this proposed order, and
the title and identification of the regulation will be revised
accordingly to include extracorporeal circuit and accessories for long-
term pulmonary/cardiac support.

DATES: Submit either electronic or written comments on this proposed
order by April 8, 2013. See section XI of this document for the
proposed effective date of a final order based on this proposed order.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2012-
N-1174, 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 way:
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-N-1174 for this order. 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: Angela Krueger, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, rm. 1666, Silver Spring, MD 20993, 301-796-6380,
angela.krueger@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

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 of 2004 (Pub. L. 108-

[[Page 1159]]

214), the Food and Drug Administration Amendments Act of 2007 (Pub. L.
110-85), and Food and Drug Administration Safety and Innovation Act
(FDASIA) (Pub. L. 112-144) established a comprehensive system for the
regulation of medical devices intended for human use. Section 513 of
the FD&C Act (21 U.S.C. 360c) established three categories (classes) of
devices, reflecting the regulatory controls needed to provide
reasonable assurance of their safety and effectiveness. The three
categories of devices are class I (general controls), class II (special
controls), and class III (premarket approval).
Under section 513 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 process. Those devices remain in class III and
require premarket approval unless, and until, the device is
reclassified into class I or II or FDA issues an order finding the
device to be substantially equivalent, in accordance with section
513(i) of the FD&C Act, to a predicate device that does not require
premarket approval. The Agency determines whether new devices are
substantially equivalent to predicate devices by means of premarket
notification procedures in section 510(k) of the FD&C Act (21 U.S.C.
360(k)) and part 807 (21 CFR part 807).
On July 9, 2012, FDASIA was enacted. Section 608(a) of FDASIA (126
Stat. 1056) amended section 513(e) of the FD&C Act, changing the
process for reclassifying a device from rulemaking to an administrative
order.
Section 513(e) of the FD&C Act governs reclassification of
preamendments devices. This section provides that FDA may, by
administrative order, 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)
of the FD&C Act or an interested person may petition FDA to reclassify
a preamendments device. The term ``new information,'' as used in
section 513(e) 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, 389-391 (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 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 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 order 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 premarket approval
application (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 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 from all affected stakeholders, including
patients, payors, and providers.
FDAMA added section 510(m) to the FD&C Act. 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

On November 2, 1979 (44 FR 63387), FDA published a proposed rule
for classification of membrane lungs for long-term pulmonary support as
class III requiring premarket approval. The Anesthesiology Device
Classification Panel recommended class III because the device is life
sustaining and life supporting and sufficient information did not exist
to determine the adequacy of general controls or to establish standards
to provide a reasonable assurance of the safety and effectiveness of
the device.
No comments were received on the proposed rule and on July 16, 1982
(47 FR 31130), a final rule was published for membrane lungs for long-
term pulmonary support, classifying these devices as class III. In
1987, FDA published a final rule amending the codified language for
this device to clarify that no effective date had been established for
the requirement for premarket approval for membrane lungs for long-term
pulmonary support devices (52 FR 17732 at 17735; May 11, 1987). In
2009, FDA published an order under sections 515(i) and 519 of the FD&C
Act (21 U.S.C. 360e and 360i) for the submission of safety and
effectiveness information on a membrane lung for long-term pulmonary
support (74 FR 16214; April 9, 2009). In response to that order, FDA
received information from one device manufacturer.

III. Device Description

A membrane lung for long-term pulmonary support refers to the
oxygenator component of an extracorporeal circuit used during long-term
procedures, commonly referred to as an ECMO. An ECMO procedure provides
assisted extracorporeal circulation and physiologic gas exchange of a
patient's blood when an acute (reversible) condition prevents the
patient's own body from providing the physiologic gas exchange needed
to sustain life. The circuit is comprised of multiple device types,
including, but

[[Page 1160]]

not limited to, an oxygenator, blood pump, cannulae, heat exchanger,
tubing, filters, monitors/detectors, and other accessories; the circuit
components and configuration (e.g., arteriovenous, veno-venous) may
differ based on the needs of the individual patient or the condition
being treated. ECMO is intended for patients with acute reversible
respiratory or cardiac failure, unresponsive to optimal ventilation
and/or pharmacologic management.
Because circuit components used with the oxygenator can be
appropriately regulated using the same set of regulatory controls, all
of the device components used in an ECMO procedure are being considered
in the scope of this proposed order as an extracorporeal circuit and
accessories for long-term pulmonary/cardiac support.

IV. Proposed Reclassification

FDA is proposing that the device subject to this proposed order be
reclassified from class III to class II. FDA is further proposing to
revise the title and identification of the regulation to reflect all
device components used in ECMO. In addition, FDA is proposing to remove
this regulation from 21 CFR part 868, Anesthesiology Devices, and add
the revised version to 21 CFR part 870, Cardiovascular Devices, to
better align this device type with other similar types of
cardiovascular devices and align the review responsibilities for this
device type. FDA believes that these devices can be utilized to provide
assisted extracorporeal circulation and physiologic gas exchange of a
patient's blood when an acute (reversible) condition prevents the
patient's own body from providing the physiologic gas exchange needed
to sustain life in conditions where imminent death is threatened by
cardiopulmonary failure in neonates and infants or where
cardiopulmonary failure results in the inability to separate from
cardiopulmonary bypass following cardiac surgery.
FDA believes that the identified special controls, in addition to
general controls, are necessary to provide reasonable assurance of
safety and effectiveness. Therefore, in accordance with sections 513(e)
and 515(i) of the FD&C Act and 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 into class II. The
Agency has identified special controls under section 513(a) of the FD&C
Act that would provide reasonable assurance of their safety and
effectiveness. The new information includes the history of use of the
circuit components, publicly available safety and effectiveness
information (as described in Section VII of this document) and the
relatively low incidence of adverse events, as discussed in the
recommendations for reclassification from the device industry
(available in docket FDA-2009-M-0101 at http://www.regulations.gov).
FDA believes that this information is sufficient to demonstrate that
the proposed special controls can effectively mitigate the risks to
health identified in section V of this document and that these special
controls, in addition to the general controls, will provide a
reasonable assurance of safety and effectiveness for ECMO devices.
FDA has considered membrane lung devices for long-term pulmonary
support in accordance with the reserved criteria and decided that the
device does require premarket notification. 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 available information, including the
recommendations of the advisory committee (panel) 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 extracorporeal circuits and accessories for long-term
pulmonary/cardiac support and determined that the following risks to
health are associated with its use:
Thrombocytopenia. Blood platelets important to the
clotting cascade may be damaged by use of the device, resulting in a
tendency toward increased bleeding.
Hemolysis. Red blood cells may be damaged by mechanical,
material, or surface features of the extracorporeal circuit.
Thrombosis/thromboembolism. Blood clots may form within
the extracorporeal circuit due to inadequate blood flow.
Hemorrhage. To keep blood from clotting in the
extracorporeal circuit, anticoagulants are generally used and may cause
increased bleeding during the procedure.
Hemodilution. Dilution of the patient's blood may be
caused by the priming of the ECMO circuit.
Inadequate gas exchange. Mechanical failure of the circuit
components may result in inadequate gas exchange.
Loss of mechanical integrity. Weakness in the connections
or construction of the circuit components could lead to leaks in the
extracorporeal circuit.
Gas embolism. Air may be introduced into the
extracorporeal circuit and result in a gas embolism.
Adverse tissue reaction. The patient-contacting materials
of the device may cause an adverse immunological or allergic reaction
in a patient if the materials are not biocompatible.
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 result in infection.
Mechanical injury to access vessels. Mechanical injury to
vessels may be caused acutely during access, or over time due to the
long-term duration of use.

VI. Summary of Reasons for Reclassification

FDA believes that extracorporeal circuits and accessories for long-
term pulmonary/cardiac support 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 for conditions where imminent death is
threatened by cardiopulmonary failure in neonates and infants or where
cardiopulmonary failure results in the inability to separate from
cardiopulmonary bypass following cardiac surgery.
FDA is proposing to rename this device to ``Extracorporeal circuit
and accessories for long-term pulmonary/cardiac support''; the current
classification regulation for this device is referred to as ``membrane
lung for long-term pulmonary support.'' For clarity, the new title for
this proposed order will be removed from 21 CFR part 868 and
redesignated to 21 CFR part 870. Section 870.4100 will be added to
reflect all device components used in ECMO.

VII. Summary of Data Upon Which the Reclassification Is Based

Since the time of the Panel recommendation, sufficient evidence has
been developed to support a reclassification of extracorporeal circuits
and accessories for long-term pulmonary/cardiac support to class II
with special controls for conditions

[[Page 1161]]

where imminent death is threatened by cardiopulmonary failure in
neonates and infants or where cardiopulmonary failure results in the
inability to separate from cardiopulmonary bypass following cardiac
surgery. FDA is familiar with the risks associated with the use of the
components of the extracorporeal circuit because the same components
are used for short-term use (durations less than 6 hours) for
cardiopulmonary bypass. In addition, the Extracorporeal Life Support
Organization registry data (Ref. 1), which provides information on over
28,000 ECMO procedures performed since 1987, and reviews of
institutional experience (Ref. 2) demonstrate a favorable benefit-risk
profile for extracorporeal circuits and accessories when used for
conditions where imminent death is threatened by cardiopulmonary
failure in neonates and infants or where cardiopulmonary failure
results in the inability to separate from cardiopulmonary bypass
following cardiac surgery.

VIII. Proposed Special Controls

FDA believes that the following special controls, in addition to
general controls, are sufficient to mitigate the risks to health
described in section V of this document:
The design characteristics of the device must ensure that
the geometry and design parameters are consistent with the intended
use;
The device must be demonstrated to be biocompatible;
Sterility and shelf life testing must demonstrate the
sterility of patient-contacting components and the shelf-life of these
components;
Nonclinical performance evaluation of the device must
demonstrate a reasonable assurance of safety and effectiveness for
mechanical integrity, durability, and reliability;
In-vivo evaluation of the device must demonstrate device
performance; and
Labeling must include a detailed summary of the
nonclinical and clinical evaluations pertinent to use of the device and
adequate instructions with respect to anticoagulation, circuit set up,
and maintenance during a procedure.
In addition, under 21 CFR 801.109, the sale, distribution, and use
of this device are restricted to prescription use.

IX. Environmental Impact

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

X. Paperwork Reduction Act of 1995

This proposed 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 21 CFR part 812 are approved under OMB
control number 0910-0078; the collections of information in part 807,
subpart E, are approved under OMB control number 0910-0120; the
collections of information in 21 CFR part 814, subpart B, are approved
under OMB control number 0910-0231; and the collections of information
under 21 CFR part 801 have are under OMB control number 0910-0485.

XI. Proposed Effective Date

FDA is proposing that any final order based on this proposal become
effective 30 days after date of publication of the final order in the
Federal Register.

XII. Comments

Interested persons may submit either electronic comments to http://www.regulations.gov or written comments regarding this document to the
Division of Dockets Management (see ADDRESSES). It is only necessary to
send one set of comments. Identify comments with the docket number
found in 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, and will be posted to the docket at http://www.regulations.gov.

XIII. 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,
and are available electronically at http://www.regulations.gov.

1. Fleming, G. M., J. G. Gurney, J. E. Donahue, et al.,
``Mechanical Component Failures in 28,171 Neonatal and Pediatric
Extracorporeal Membrane Oxygenation Courses From 1987 to 2006,''
Pediatric Critical Care Medicine Journal, vol. 10, pp. 439-444, July
2009.
2. Cook, L. N., ``Update on Extracorporeal Membrane
Oxygenation,'' Paediatric Respiratory Reviews, vol. 5, suppl. A, pp.
S329-S337, 2004.

List of Subjects in 21 CFR Parts 868 and 870

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 parts 868 and 870 be amended as follows:

PART 868--ANESTHESIOLOGY DEVICES

0
1. The authority citation for 21 CFR part 868 continues to read as
follows:

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

Sec. 868.5610 [Removed]

0
2. Remove Sec. 868.5610.

PART 870--CARDIOVASCULAR DEVICES

0
3. The authority citation for 21 CFR part 870 continues to read as
follows:

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

0
4. Add Sec. 870.4100 to subpart E to read as follows:

Sec. 870.4100 Extracorporeal circuit and accessories for long-term
pulmonary/cardiac support.

(a) Identification. An extracorporeal circuit and accessories for
long-term pulmonary/cardiac support (>6 hours) is a system of devices
that provides assisted extracorporeal circulation and physiologic gas
exchange of the patient's blood in conditions where imminent death is
threatened by cardiopulmonary failure in neonates and infants or where
cardiopulmonary failure results in the inability to separate from
cardiopulmonary bypass following cardiac surgery. An acute reversible
or treatable cause of respiratory and/or cardiac failure should be
evident, and the subject should demonstrate unresponsiveness to maximum
medical or ventilation therapy. The main components of the system
include the console (hardware), software, and disposables, including
but not limited to, an oxygenator, blood pump, heat exchanger,
cannulae, tubing, filters, and other accessories (e.g., monitors,
detectors, sensors, connectors).
(b) Class II (special controls). The special controls for this
device are:
(1) The design characteristics of the device must ensure that the
geometry and design parameters are consistent with the intended use;
(2) The device must be demonstrated to be biocompatible;
(3) Sterility and shelf life testing must demonstrate the sterility
of patient-

[[Page 1162]]

contacting components and the shelf-life of these components;
(4) Non-clinical performance evaluation of the device must provide
a reasonable assurance of safety and effectiveness for mechanical
integrity, durability, and reliability;
(5) In-vivo evaluation of the device must demonstrate device
performance; and
(6) Labeling must include a detailed summary of the nonclinical and
clinical evaluations pertinent to use of the device and adequate
instructions with respect to anticoagulation, circuit set up, and
maintenance during a procedure.

Dated: January 2, 2013.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2013-00086 Filed 1-7-13; 8:45 am]
BILLING CODE 4160-01-P