[Federal Register Volume 78, Number 5 (Tuesday, January 8, 2013)]
[Proposed Rules]
[Pages 1158-1162]
From the Federal Register Online via the Government Publishing 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