[Federal Register Volume 69, Number 37 (Wednesday, February 25, 2004)]
[Proposed Rules]
[Pages 8600-8604]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-3858]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 870 and 882

[Docket No. 2003N-0567]


Cardiovascular and Neurological Devices; Reclassification of Two 
Embolization Devices

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to 
reclassify two embolization devices to change the names of the devices, 
revise the identification of the devices, and reclassify the two 
devices from class III (premarket approval) into class II (special 
controls). The vascular embolization device (previously the arterial 
embolization device) is intended to control hemorrhaging due to 
aneurysms, certain tumors, and arteriovenous malformations. The 
neurovascular embolization device (previously the artificial 
embolization device) is intended to permanently occlude blood flow to 
cerebral aneurysms and cerebral arteriovenous malformations. These 
reclassifications are being proposed under the agency's own initiative 
under the Federal Food, Drug, and Cosmetic Act (the act), as amended by 
the Medical Device Amendments of 1976 (the 1976 amendments), the Safe 
Medical Devices Act of 1990 (the SMDA), the Food and Drug 
Administration Modernization Act of 1997 (FDAMA), and the Medical 
Device User Fee and Modernization Act of 2002 (MDUFMA) based on new 
information. Elsewhere in this issue of the Federal Register, FDA is 
publishing a notice of availability of the draft guidance document that 
the agency proposes to use as a special control for these devices.

DATES: Submit written or electronic comments on the proposed rule by 
May 25, 2004.

ADDRESSES: Submit written comments to the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
rm. 1061, Rockville, MD 20852. Submit electronic comments to: http://www.fda.gov/dockets/ecomments.

FOR FURTHER INFORMATION CONTACT: Peter L. Hudson, Center for Devices 
and Radiological Health (HFZ-410), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 301-594-3090.

SUPPLEMENTARY INFORMATION:

I. Regulatory Authorities

    The act, as amended by the 1976 amendments (Public Law 94-295), the 
SMDA (Public Law 101-629), the FDAMA (Public Law 105-115), and MDUFMA 
(Public Law 107-250) established a comprehensive system for the 
regulation of medical devices intended for human use. Section 513 of 
the act (21 U.S.C. 360c) established three categories (classes) of 
devices, depending on 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 act, devices that were in commercial 
distribution before May 28, 1976 (the date of enactment of the 1976 
amendments), 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 classified 
automatically by statute (section 513(f) of the act) into class III 
without any FDA rulemaking process. Postamendments devices require 
premarket approval, unless FDA issues an order finding the device to be

[[Page 8601]]

substantially equivalent, in accordance with section 513(i) of the act, 
to a predicate device that does not require premarket approval. The 
agency determines whether new devices are substantially equivalent to 
previously offered devices by means of premarket notification 
procedures in section 510(k) of the act (21 U.S.C. 360(k)) and 21 CFR 
part 807 of the regulations.
    A preamendments device that has been classified into class III may 
be marketed, by means of premarket notification procedures, without 
submission of a premarket approval application (PMA) until FDA issues a 
final regulation under section 515(b) of the act (21 U.S.C. 360e(b)) 
requiring premarket approval.
    In 1990, the SMDA added section 515(i) to the act. This section 
requires FDA to issue an order to manufacturers of preamendments class 
III devices for which no final regulation requiring the submission of 
PMAs has been issued to submit to the agency a summary of, and a 
citation to, any information known or otherwise available to them 
respecting such devices, including adverse safety and effectiveness 
information that has not been submitted under section 519 of the act 
(21 U.S.C. 360i). Section 519 of the act requires manufacturers, 
importers, and device user facilities to submit adverse event reports 
of certain device-related events and reports of certain corrective 
actions taken. Section 515(i) of the act also directs FDA to either 
revise the classification of the device into class I or class II or 
require the device to remain in class III and establish a schedule for 
the issuance of a rule requiring the submission of PMAs for those 
devices.
    In the Federal Register of May 6, 1994 (59 FR 23731), FDA announced 
the availability of a document setting forth its strategy for 
implementing the provisions of the SMDA that require FDA to review the 
classification of preamendments class III devices. Under this plan, the 
agency divided preamendments class III devices into the following three 
groups: Group 1 devices are devices that FDA believes raise significant 
questions of safety and/or effectiveness, but are no longer used or are 
in very limited use; group 2 devices are devices that FDA believes have 
a high potential for being reclassified into class II; and group 3 
devices are devices that FDA believes are currently in commercial 
distribution and are not likely candidates for reclassification.
    In the Federal Register of August 14, 1995 (60 FR 41984 and 41986), 
FDA published two orders for certain class III devices requiring the 
submission of safety and effectiveness information in accordance with 
the preamendments class III strategy for implementing section 515(i) of 
the act. FDA published two updated orders in the Federal Register of 
June 13, 1997 (62 FR 32352 and 32355). The orders describe in detail 
the format for submitting the type of information required by section 
515(i) of the act so that the information submitted would clearly 
support reclassification or indicate that a device should be retained 
in class III. The orders also scheduled the required submissions in 
groups, at 6-month intervals, beginning with August 14, 1996. The 
devices proposed in this regulation for reclassification are included 
in group 3.
    Reclassification of classified preamendments devices is governed by 
section 513(e) of the act. This section provides that FDA may, by 
rulemaking, reclassify a device (in a proceeding that parallels the 
initial classification proceeding) based upon ``new information.'' The 
reclassification can be initiated by FDA or by the petition of an 
interested person. The term ``new information,'' as used in section 
513(e) of the act, includes information developed as a result of a re-
evaluation 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).)
    Re-evaluation of the data previously before the agency is an 
appropriate basis for subsequent regulatory action where the re-
evaluation is made in light of changes in ``medical science.'' (See 
Upjohn v. Finch, supra, 422 F.2d at 951.) However, regardless of 
whether data before the agency are past or new data, the ``new 
information'' upon which reclassification under section 513(3) of the 
act is based must consist of ``valid scientific evidence'' as defined 
in section 513(a)(3) of the act and 21 CFR 860.7(c)(2). FDA relies upon 
``valid scientific evidence'' in the classification process to 
determine the level of regulation for devices. For the purpose of 
reclassification, the valid scientific evidence upon which the agency 
relies must be publicly available. Publicly available information 
excludes trade secret and/or confidential commercial information, and 
other information that may be protected. (See section 520(c) of the act 
(21 U.S.C. 360j(c)).)

II. Regulatory History of the Devices

A. Vascular (Arterial) Embolization Device

    In the Federal Register of February 5, 1980 (45 FR 7937), FDA 
issued a final rule classifying the arterial embolization device, into 
class III (Sec.  870.3300 (21 CFR 870.3300)). The preamble to the 
proposed rule to classify the device (44 FR 13363, March 9, 1979) 
included the recommendations of the Cardiovascular Device 
Classification Panel (the Cardiovascular Panel) regarding the 
classification of the device. The Cardiovascular Panel recommended that 
the device be classified into class III and identified the following 
risks to health associated with the device: Thromboembolization, 
inadvertent embolization and infarction, vessel perforation, 
progressive granulomatous inflammation, and infection. FDA agreed with 
the Cardiovascular Panel's recommendation.

B. Neurovascular (Artificial) Embolization Device

    In the Federal Register of September 4, 1979 (44 FR 51777), FDA 
issued a final rule classifying the artificial embolization device into 
class III (Sec.  882.5950 (21 CFR 882.5950)). The preamble to the 
proposed rule to classify the device (43 FR 55730, November 28, 1978) 
included the recommendations of the Neurological Devices Classification 
Panel (the Neurological Panel), an FDA advisory committee regarding the 
classification of the device. The Neurological Panel recommended that 
the device be classified into class III and identified tissue 
infarction and tissue toxicity as risks to health associated with use 
of the device. FDA agreed with the Neurological Panel's recommendation.

III. Device Descriptions

    FDA is proposing the following revised device names and 
identifications based on the agency's review:
    FDA is proposing to rename the arterial embolization device as 
``vascular embolization device'' and the artificial embolization device 
as the ``neurovascular embolization device.''
    A vascular embolization device is an intravascular implant intended 
to control hemorrhaging due to aneurysms, certain types of tumors 
(e.g., nephroma, hepatoma, uterine fibroids), and arteriovenous 
malformations. This does not include cyanoacrylates and other embolic 
agents, which act by polymerization or precipitation. Embolization 
devices used in neurovascular applications are also not

[[Page 8602]]

included in this classification. (See Sec.  882.5950.)
    A neurovascular embolization device is an intravascular implant 
intended to permanently occlude blood flow to cerebral aneurysms and 
cerebral arteriovenous malformations. This does not include 
cyanoacrylates and other embolic agents, which act by polymerization or 
precipitation. Embolization devices used in other vascular applications 
are also not included in this classification. (See Sec.  870.3300.)
    The proposed names of vascular embolization device and 
neurovascular embolization device and the proposed device 
identifications more accurately reflect the intended uses of the 
legally marketed arterial and artificial embolization devices, 
respectively. Postamendments class III vascular and neurovascular 
embolization devices, such as cyanoacrylates and other embolization 
devices, which act by polymerization and precipitation, continue to 
require premarket approval.

IV. Recommendation of the Neurological Panel

    At a public meeting on June 12, 1998, the Neurological Panel 
recommended that the neurovascular (artificial) embolization device be 
reclassified from class III into class II (Ref. 1). The Neurological 
Panel believed that class II with the special controls, in addition to 
the general controls, would reasonably assure the safety and 
effectiveness of the device. The Neurological Panel also recommended 
that the special controls for the device be labeling, sterilization, 
and biocompatibility.
    At another public meeting on September 16 and 17, 1999 (Ref. 2), 
the Neurological Panel made recommendations on FDA's draft guidance 
document entitled ``Guidance Document for Neurological Embolization 
Devices.'' The draft guidance document addressed the Neurological 
Panel's June 12, 1998, special controls recommendations for the device. 
Based on the Neurological Panel's recommendations and public comments 
on the draft guidance document, FDA revised the draft guidance document 
and issued it on November 1, 2000.
    While the Panel's recommendation was specifically for the 
neurovascular (artificial) embolization device, because of the 
similarity of the vascular (arterial) embolization device to the 
neurovascular embolization device, in its intended use, design, risks 
to health, controls to mitigate the risks to health, and benefits, FDA 
has determined that the Neurological Panel's reclassification 
recommendation for the neurovascular embolization device is also 
relevant to the vascular embolization device.

V. Risks to Health

    After considering the information in one 515(i) submission that 
addressed both device classifications (Ref. 3) and two other 515(i) 
submissions that addressed the neurovascular embolization device (Refs. 
4 and 5), the Neurological Panel's 1998 and 1999 recommendations, as 
well as the published literature and Medical Device Reports, FDA has 
evaluated the risks to health associated with use of the vascular and 
the neurovascular embolization devices. FDA believes that the following 
are risks to health associated with use of both device types: Vessel 
perforation or rupture, unintended thrombosis, adverse tissue reaction, 
infection, and hematoma formation. These risks to health are due to a 
combination of factors relating to the severely diseased, damaged, or 
malformed blood vessel; clinician experience; and the device.

A. Blood Vessel Perforation or Rupture

    Blood vessel perforation or rupture may cause life-threatening 
hemorrhage. Blood vessel perforation may result from improper use of 
the delivery catheter, device-induced mechanical injury to the 
endothelial cells lining the blood vessel, or vasospasm. Blood vessel 
perforation or rupture may require surgery to correct this damage.

B. Unintended Thrombosis

    Unintended thrombosis from implantation of an embolization device 
may cause distal tissue injury (i.e., ischemia and necrosis), which for 
the cerebral embolization may cause neurological deficits leading to 
cranial nerve palsy, visual impairment, stroke, infarct, unintended 
injury to organs, pulmonary embolization, or death. Incorrect device 
selection, device misplacement, device migration, device fracture, 
inadequate visualization of the device, or use of an inappropriate 
catheter delivery system may cause unintended thrombosis.

C. Adverse Tissue Reaction

    Adverse tissue reaction is a risk to health common to all implanted 
devices. The implantation of embolization devices will elicit a mild 
inflammatory reaction typical of a normal foreign body response. 
Incompatible materials or impurities in the materials may increase the 
severity of a local tissue reaction or cause a systemic tissue 
reaction.

D. Infection

    Infection of the soft tissue and fever are potential risks to 
health associated with all surgical procedures and implanted devices. 
Incompatible or impure material composition may irritate the 
vasculature, which could increase the risk of infection. Improper 
sterilization or packaging may also increase the risk of infection. Use 
of a device that is not pyrogen-free may elicit a fever response.

E. Hematoma Formation

    Hematoma formation at the delivery catheter entry site, usually 
groin access to the femoral artery, is the result of internal bleeding.

VI. Summary of the Reasons for the Reclassification

    FDA believes that the vascular embolization device and the 
neurovascular embolization device should be reclassified into class II 
because special controls, in addition to general controls, provide 
reasonable assurance of the safety and effectiveness of the device, and 
there is sufficient information to establish special controls to 
provide such assurance.

VII. Summary of the Data Upon Which the Reclassification is Based

    In addition to the potential risks to health associated with 
implantation of the vascular and neurovascular embolization devices 
described in section V of this document, there is reasonable knowledge 
of the benefits of the devices. Specifically, the vascular and 
neurovascular embolization devices may prevent life-threatening 
hemorrhage, reduce surgical morbidity and blood loss, and may reduce or 
relieve symptoms when surgical resection is not possible.

VIII. Special Controls

    FDA believes that the guidance document entitled ``Class II Special 
Controls Guidance Document: Vascular and Neurovascular Embolization 
Devices'' (the class II special controls guidance document) in addition 
to general controls, can address the risks to health described in 
section V of this document. Because of the similarity of the two 
devices in intended use, design, risks to health, controls to mitigate 
the risks to health, and benefits, FDA has determined that the 
Neurological Panel's special controls recommendation for the 
neurovascular embolization device is also relevant to the vascular 
embolization device. Elsewhere in this issue of the Federal Register, 
FDA is publishing a notice of availability of this draft class II 
special

[[Page 8603]]

controls guidance document that the agency is proposing to use as the 
special control for these devices.
    The draft guidance document contains specific recommendations with 
regard to device performance testing and other information in a 
premarket notification (510(k)) submission. Particular sections of the 
guidance document address the following topics for both embolization 
devices: Preclinical testing (including biocompatibility), sterility, 
animal testing, clinical testing, and labeling. In the table 1 of this 
document, FDA has identified the risks to health associated with the 
use of these devices in the first column and the recommended mitigation 
measures identified in the class II special controls guidance document 
in the second column. These recommendations will also help ensure that 
the device has appropriate performance characteristics and labeling for 
its use. Following the effective date of any final reclassification 
rule based on this proposal, any firm submitting a 510(k) submission 
for these embolization devices will need to address the issues covered 
in the class II special controls guidance document. However, the firm 
need only show that its device meets the recommendations of the class 
II special controls guidance document or in some other way provides 
equivalent assurances of safety and effectiveness.

      Table 1.--Risks to Health and Recommended Mitigation Measures
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           Risk to health              Recommended mitigation measures
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Blood vessel perforation or rupture  Preclinical testing, Animal
                                      testing, Clinical testing,
                                      Labeling
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Unintended thrombosis                Preclinical testing, Animal
                                      testing, Clinical testing,
                                      Labeling
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Adverse tissue reaction              Preclinical testing, Animal
                                      testing, Clinical testing
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Infection                            Sterility
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Hematoma formation                   Animal testing, Clinical testing,
                                      Labeling
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IX. FDA's Tentative Findings

    FDA believes the vascular and the neurovascular embolization 
devices should be reclassified into class II because special controls, 
in addition to general controls, can provide reasonable assurance of 
the safety and effectiveness of the devices and there is sufficient 
information to establish special controls to provide such assurance. 
FDA, therefore, is proposing to reclassify these devices into class II 
and establish the class II special controls guidance document as a 
special control for the devices.
    For the convenience of the reader, FDA is also adding new Sec.  
870.1(e) and Sec.  882.1(e) to inform the reader where to find guidance 
documents referenced in parts 870 and 882.

X. Effective Date

    FDA proposes that any final rule that may issue based on this 
proposal become effective 30 days after its date of publication in the 
Federal Register.

XI. Environmental Impact

    The agency has determined under 21 CFR 25.34(b) that this proposed 
reclassification 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.

XII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and 
the Unfunded Mandates Reform Act of 1995 (Public Law 104-4). Executive 
Order 12866 directs 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 consistent with the regulatory philosophy and 
principles identified in the Executive order. In addition, the proposed 
rule is not a significant regulatory action as defined by the Executive 
order and so is not subject to review under the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Reclassification of these devices from class III to 
class II will relieve all manufacturers of the device types of the 
costs of complying with the premarket approval requirements in section 
515 of the act. Because reclassification will reduce regulatory costs 
with respect to this device, it will impose no significant economic 
impact on any small entities, and it may permit small potential 
competitors to enter the marketplace by lowering their costs. The 
agency therefore certifies that this proposed rule, if finalized, would 
not have a significant economic impact on a substantial number of small 
entities. In addition, this proposed rule, if finalized, would not 
impose costs of $100 million or more on either the private sector or 
State, local, and tribal governments in the aggregate, and therefore a 
summary statement or analysis under section 202(a) of the Unfunded 
Mandates Reform Act of 1995 is not required.

XIII. Paperwork Reduction Act of 1995

    This proposed rule does not contain information collection 
provisions that are subject to review by the Office of Management and 
Budget under the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520).

XIV. Submission of Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified 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.

XV. References

    The following references are on display at 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:
    1. Neurological Devices Panel, transcript, June 12, 1998, pp. 1-
124.
    2. Neurological Devices Panel, transcript, September 17, 1999, 
pp. 9-11 and 101-152.
    3. 515(i) submission submitted by Target Therapeutics, Inc., 
Fremont, CA, February 12, 1998.
    4. 515(i) submission submitted by Cordis Endovascular Corp., 
Miami Lakes, FL, February 13, 1998.
    5. 515 (i) submission submitted by Cook, Inc., Bloomington, IN, 
February 28, 1998.

List of Subjects in 21 CFR Parts 870 and 882

    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 870 and 882 be amended as follows:

[[Page 8604]]

PART 870--CARDIOVASCULAR DEVICES

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

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
    2. Section 870.1 is amended by adding paragraph (e) to read as 
follows:


Sec.  870.1  Scope.

* * * * *
    (e) Guidance documents referenced in this part are available on the 
Internet at http://www.fda.gov/cdrh/guidance.html.
    3. Section 870.3300 is revised in subpart D to read as follows:


Sec.  870.3300  Vascular embolization device.

    (a) Identification. A vascular embolization device is an 
intravascular implant intended to control hemorrhaging due to 
aneurysms, certain types of tumors (e.g., nephroma, hepatoma, uterine 
fibroids), and arteriovenous malformations. This does not include 
cyanoacrylates and other embolic agents, which act by polymerization or 
precipitation. Embolization devices used in neurovascular applications 
are also not included in this classification. (See 21 CFR 882.5950.)
    (b) Classification. Class II (special controls). The special 
control for this device is the FDA guidance document entitled ``Class 
II Special Controls Guidance Document: Vascular and Neurovascular 
Embolization Devices.'' For availability of this guidance document, see 
Sec.  870.1(e).

PART 882--NEUROLOGICAL DEVICES

    4. The authority citation for 21 CFR part 882 continues to read as 
follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 371.
    5. Section 882.5950 is revised to read as follows:


Sec.  882.5950  Neurovascular embolization device.

    (a) Identification. A neurovascular embolization device is an 
intravascular implant intended to permanently occlude blood flow to 
cerebral aneurysms and cerebral arteriovenous malformations. This does 
not include cyanoacrylates and other embolic agents, which act by 
polymerization or precipitation. Embolization devices used in other 
vascular applications are also not included in this classification, see 
Sec.  870.3300.
    (b) Classification. Class II (special controls). The special 
control for this device is the FDA guidance document entitled ``Class 
II Special Controls Guidance Document: Vascular Embolization Devices 
and Neurovascular Embolization Devices.'' For availability of this 
guidance document, see Sec.  882.1(e).

    Dated: February 11, 2004.
Beverly Chernaik Rothstein,
Acting Deputy Director for Policy and Regulations, Center for Devices 
and Radiological Health.
[FR Doc. 04-3858 Filed 2-24-04; 8:45 am]
BILLING CODE 4160-01-S