General and Plastic Surgery Devices; Reclassification of the Tissue Adhesive for Topical Approximation of Skin Device, 31027-31033 [E8-12078]

Agencies

• Food and Drug Administration
• DEPARTMENT OF HEALTH AND HUMAN SERVICES

[Federal Register Volume 73, Number 105 (Friday, May 30, 2008)]
[Rules and Regulations]
[Pages 31027-31033]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: E8-12078]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 878

[Docket No. FDA-2006-P-0140] (formerly Docket No. 2006P-0071)


General and Plastic Surgery Devices; Reclassification of the 
Tissue Adhesive for Topical Approximation of Skin Device

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is reclassifying the 
device type, tissue adhesive for the topical approximation of skin, 
from class III (premarket approval) into class II (special controls). 
Tissue adhesives for non-topical uses remain in class III and continue 
to require premarket approval applications (PMAs). FDA is proposing 
this reclassification in accordance with the Federal Food, Drug, and 
Cosmetic Act (the act). Elsewhere in this issue of the Federal 
Register, FDA is announcing the availability of a guidance document 
entitled ``Class II Special Controls Guidance Document: Tissue Adhesive 
for the Topical Approximation of Skin'' that will serve as the special 
control for the reclassified device type.

DATES: This final rule is effective June 30, 2008.

FOR FURTHER INFORMATION CONTACT: George J. Mattamal, Center for Devices 
and Radiological Health (HFZ-410), Food and Drug Administration, 9200 
Corporate Blvd., Rockville, MD 20850, 240-276-3619.

SUPPLEMENTARY INFORMATION:

I. Regulatory Authorities

    The act, as amended by the Medical Device Amendments of 1976 (the 
1976 amendments) (Public Law 94-295), the Safe Medical Devices Act of 
1990 (SMDA) (Public Law 101-629), and the Food and Drug Administration 
Modernization Act of 1997 (FDAMA) (Public Law 105-115), among other 
amendments, 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).
    The 1976 amendments broadened the definition of ``device'' in 
section 201(h) of the act (21 U.S.C. 321(h)) to include certain 
articles that were once regulated as drugs. Under the 1976 amendments, 
Congress classified all transitional devices, i.e., those devices 
previously regulated as new drugs, into class III. SMDA amended section 
520(l) of the act (21 U.S.C. 360j(l)) to direct FDA to collect certain 
safety and effectiveness information from the manufacturers of 
transitional devices still remaining in class III to determine whether 
the devices should be reclassified into class II (special controls) or 
class I (general controls). The legislative history of the SMDA 
reflects congressional concern that many transitional devices were not 
appropriately regulated in class III (H. Rept. 808, 101st Cong., 2d 
sess. 26-27 (1990); S. Rept. 513, 101st Cong., 2d sess. 27 (1990)).
    Accordingly, in the Federal Register of November 14, 1991 (56 FR 
57960), FDA issued an order under section 520(l)(5)(A) of the act, 
requiring manufacturers of transitional devices to submit to FDA a 
summary of and a citation to any information known or otherwise 
available to them respecting the devices, including adverse safety or 
effectiveness information, that had not

[[Page 31028]]

been submitted under section 519 of the act (21 U.S.C. 360i). 
Manufacturers were to submit the summaries and citations to FDA by 
January 13, 1992. By notice published in the Federal Register of March 
10, 1992 (57 FR 8462), FDA extended the reporting period to March 31, 
1992.
    Section 520(l)(5)(B) of the act provides that, after the issuance 
of an order requiring manufacturers to submit any information known or 
otherwise available respecting the devices, but before December 1, 
1992, FDA was to publish regulations either leaving transitional class 
III devices in class III or reclassifying them into class I or II. 
Subsequently, as permitted by section 520(l)(5)(C) of the act, in the 
Federal Register of November 30, 1992 (57 FR 56586), the agency 
published a notice extending the period for issuing such regulations 
until December 1, 1993, but did not publish the regulations before 
December 1, 1993.

II. Regulatory Background of the Device

    Transitional devices, those devices formerly regulated as drugs, 
were classified into class III by the statute and premarket approval 
was immediately required (section 520(l) of the act). The Federal 
Register of December 16, 1977 (42 FR 63472), identified certain 
transitional devices and stated the following: ``The lists contained in 
this notice may not be an exhaustive inventory of products subject to 
section 520(l) of the act.'' This notice did not specifically list 
``Tissue Adhesives.'' The investigational new drug (IND) and new drug 
applications (NDAs) for transitional devices were shortly thereafter 
transferred to FDA's Center for Devices and Radiological Health 
(formerly the Bureau of Medical Devices). Applications for tissue 
adhesives were included in this transfer. In a January 19, 1982, 
preamble to a proposed rule classifying other devices (47 FR 2810), 
``tissue adhesive for use in general surgery,'' was identified as a 
transitional device, but listed under injectable silicone. Since 
enactment of the 1976 amendments, FDA has approved several PMAs and PMA 
supplements authorizing the commercial distribution of tissue adhesives 
in the United States.

III. Description of the Device

    FDA has referred to this device type, under review for 
reclassification, in previous notices as ``tissue adhesive for use in 
general surgery''; however, FDA is now revising the name and 
identification to more accurately identify the device type. The device, 
reclassified into class II, would be:
    Tissue adhesive for the topical approximation of skin. A tissue 
adhesive for the topical approximation of skin is a device intended for 
topical closure of surgical incisions, including laparoscopic 
incisions, and simple traumatic lacerations that have easily 
approximated skin edges. Tissue adhesives for the topical approximation 
of skin may be used in conjunction with, but not in place of, deep 
dermal stitches.
    FDA is also issuing the following identification for the devices 
that will remain in class III:
    A tissue adhesive for non-topical use, including adhesives intended 
for use in the embolization of brain arteriovenous malformation or 
ophthalmic surgery, is a device used for adhesion of internal tissues 
and vessels.

IV. Recommendation of the Panel

    On February 9, 2006, Regulatory & Clinical Research Institute, Inc. 
(RCRI), Minneapolis, MN, submitted a petition (Docket No. 2006P-0071) 
to FDA to reclassify tissue adhesive for soft tissue approximation from 
``Class III to Class II (special controls)'' (Ref. 1). On May 15, 2006, 
the petitioner amended its petition to include several references from 
the scientific literature cited in the original petition (Ref. 2). On 
July 18, 2006, the petitioner again amended its petition to clarify 
that the use it was proposing for reclassification was only the topical 
approximation of skin (Ref. 3).
    In response to the petition, FDA consulted with the FDA's General 
and Plastic Surgery Devices Panel (the Panel), regarding 
reclassification of this device type. The Panel discussed the device 
type at an August 25, 2006, public meeting and unanimously recommended 
that the tissue adhesive for the topical approximation of skin be 
reclassified from class III into class II. The Panel also recommended 
that a class II guidance document, which the Panel thought should 
include several voluntary consensus standards, be the special control 
for the device. The Panel based the recommendations on the information 
provided by FDA; the presentations to the panel by the petitioner, 
other manufacturers, and FDA; the Panel's deliberations at the meeting; 
and the Panel's personal experience with the use of devices for the 
topical approximation of skin. The Panel did not consider the 
reclassification of any other use of tissue adhesives.
    Accordingly, in the Federal Register of July 3, 2007 (72 FR 36398), 
FDA issued a proposed rule to reclassify the device, tissue adhesive 
for the topical approximation of skin, from class III (premarket 
approval) into class II (special controls). Tissue adhesive for non-
topical uses would remain in class III and continue to require PMAs.

V. Comments

    FDA invited interested persons to comment on the proposed rule by 
September 4, 2007. FDA received two comments on the proposed rule. The 
following is a summary of the comments and FDA's responses. Elsewhere 
in this issue of the Federal Register, portions of the comments which 
address only the draft guidance document are addressed in the notice of 
availability announcing the special controls guidance document.
    (Comment 1) One comment supported the reclassification of tissue 
adhesives. The comment noted that the tissue adhesives approved by FDA 
have had a long history of safety. The comment suggested that tissue 
adhesives made of other cyanoacrylates with different alkyl groups may 
have additional benefits for patients. The comment also said that bench 
testing is more useful than clinical testing to evaluate substantial 
equivalence due to the many uncontrolled variables. The comment said 
that manufacturers of new tissue adhesives should be permitted to 
market their devices through a premarket notification if they are able 
to demonstrate that their devices are substantially equivalent to the 
marketed predicate devices.
    (Response) FDA agrees that these type devices should be 
reclassified and intends that manufacturers who are able to demonstrate 
substantial equivalence to marketed devices within the reclassified 
generic type will be permitted to market their devices.
    (Comment 2) One comment objected that FDA improperly designated the 
tissue adhesive for the topical approximation of skin as a transitional 
device. The comment said that the tissue adhesive for the topical 
approximation of skin does not meet the definition of a transitional 
device in section 520(l) of the act. The comment noted that an NDA for 
a tissue adhesive was submitted before the enactment of the 1976 
amendments but was subsequently withdrawn before the enactment date. 
The comment said that, in order for the device to be a transitional 
device, it is necessary for an IND to have been in effect or for an NDA 
to have been pending or approved on the enactment date. The comment 
said that tissue adhesives are devices automatically classified into 
class III under section 513(f)(1) of the act.
    (Response) Section 520(l)(1)(B) provides that a device is a 
transitional

[[Page 31029]]

device if ``an application [under section 505(b) of the act was filed 
on or before the enactment date [of the Medical Device Amendments of 
1976] and with respect to which no order of approval or refusing to 
approve had been issued on such date* * *.'' The comment agrees that an 
application was filed before the enactment date. It is also clear that 
no order of approval or refusing to approve had been issued before the 
enactment date. The plain words of the statute do not require that an 
application be pending on the date of enactment. As noted previously, 
FDA published a document on January 19, 1982 identifying, among other 
devices, tissue adhesives as transitional devices. FDA did not receive 
any objections to this designation until the comment on this proposed 
rule. Furthermore, even if the device would be considered a 
postamendments device under section 513(f) of the act, the procedures 
that FDA followed would be sufficient to reclassify the device. FDA did 
not follow ``truncated procedures'' to reclassify the device under the 
transitional device provisions. FDA referred the petition to an 
advisory panel that made a recommendation after holding an open public 
meeting. FDA published the panel recommendation along with the proposed 
rule and provided interested persons 60 days to comment on the 
proposal. The criteria for reclassifying a device into class II are 
identical for transitional devices under section 520(l) of the act and 
postamendments devices under section 513(f) of the act.
    (Comment 3) One comment said that FDA failed to instruct the panel 
on the appropriate legal standard for reclassification. The comment 
said that the panel transcript and briefing memorandum show that FDA 
did not instruct the panel that a reclassification recommendation must 
be based on valid scientific evidence.
    (Response) FDA disagrees. The panel was instructed properly. FDA 
conducts training sessions prior to the panel meeting for panel members 
before they undertake their duties. Training for panels considering the 
reclassification of a transitional device type consists of procedures 
for the reclassification of a device type, including a transitional 
device type, and the appropriate regulatory controls for each class of 
device. Moreover, it is FDA's responsibility to make reclassification 
decisions after receiving a panel recommendation. In accordance with 
Sec.  860.7(c)(1) (21 CFR 860.7(c)(1)) the agency relied on valid 
scientific evidence in determining that special controls, in addition 
to general controls, would provide reasonable assurance of the safety 
and effectiveness of the device.
    (Comment 4) One comment said that FDA did not identify an 
appropriate generic type of device that could be reclassified. The 
comment said that existing tissue adhesives are significantly different 
in composition and could not be combined into a single generic type of 
device. The comment also said there is insufficient publicly available 
formulation and manufacturing information to establish a generic type 
of device. Finally, the comments said that even minor differences in 
product composition can affect the performance of the device.
    (Response) FDA disagrees with this comment. The FDA classification 
regulations (21 CFR 860.3(i)) define generic type of device as ``a 
grouping of devices that do not differ significantly in purpose, 
design, materials, energy source, function, or any other feature 
related to safety and effectiveness, and for which similar regulatory 
controls are sufficient to provide reasonable assurance of safety and 
effectiveness.'' It is not necessary that devices be identical in order 
to fit within the same generic type. FDA believes that there is 
sufficient publicly available information from currently marketed 
tissue adhesives to show that they do not differ significantly in 
design, materials, and function and that similar regulatory controls 
are sufficient to provide reasonable assurance of their safety and 
effectiveness. A manufacturer who wishes to market a new device will 
need to show in a premarket notification that its device is 
substantially equivalent in safety and effectiveness to a marketed 
predicate device.
    (Comment 5) Two comments said that there was insufficient valid 
scientific evidence to support the reclassification. One comment noted 
that three of the articles submitted are not reports of prospective 
clinical trials. The comment described one of the articles as a general 
discussion of tissue adhesives, the second article as a brief 
description of one facility's 6-month experience with tissue adhesives, 
and the third article as a retrospective review of eight different 
clinical studies. The comment further said the 6 FDA-designated 
representative articles that discuss prospective clinical studies 
involve limited numbers of subjects with a total of 60 to 100 subjects 
in each study.
    (Response) FDA disagrees with this comment. FDA regulations (Sec.  
860.7(b)(2)) define valid scientific evidence as:
    ``* * *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. The evidence 
required may vary according to the characteristics of the device, its 
conditions of use, the existence and adequacy of warnings and other 
restrictions, and the extent of experience with its 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* 
* *.''
    FDA believes that the evidence on the record falls within this 
definition of valid scientific evidence. The shortcomings of the 
information alleged by the comment do not take this information out of 
the category of valid scientific evidence. Literature available to FDA 
and the Panel included over 1,500 published articles that reported on 
the use of multiple adhesives in over 5,900 procedures (over 5,500 
patients), with more than half evaluated in prospective randomized 
trials. The study protocols included primary endpoints such as 
cosmesis, dehiscence, and healing time for the topical skin 
approximations. As defined in Sec.  860.7(c)(2), randomized prospective 
trials and peer-reviewed literature constitute valid scientific 
evidence.
    (Comment 6) One comment said that the performance parameters for 
the device described in the proposal are incomplete. The comment said 
that missing performance parameters include adherence and endurance 
(how long the product will remain intact once applied); the ability to 
potentiate infection; the ability to maintain a microbial barrier; and 
how the skin reacts to the stabilizing agents. The comment also said 
that publicly available scientific literature does not yield ranges of 
values that would constitute acceptable performance on required tests 
to demonstrate that performance parameters are met.
    (Response) FDA disagrees with this comment. FDA believes that the 
FDA recommendations for premarket notifications in the special controls 
guidance as well as general controls will adequately address all 
appropriate performance parameters. Manufacturers who are proposing the 
introduction of a new tissue adhesive will need to demonstrate 
substantial equivalence to a

[[Page 31030]]

legally marketed predicate device in all safety and effectiveness 
aspects before FDA will issue a substantial equivalence order. All 
manufacturers submitting 510(k)s will need to demonstrate the 
performance characteristics of the device related to adhesive strength, 
(i.e., tensile strength, shear strength, peel adhesion strength, and 
impact strength); hydrolytic degradation (i.e., the amount of 
formulation additives, monomer impurities, and degradation products); 
heat of polymerization; shelf life; and biocompatibility. FDA believes 
that these performance characteristics will directly or indirectly 
address the performance parameters identified in the comment. Where 
these performance characteristics are shown sufficiently different from 
currently legally marketed devices, the special controls guidance 
document indicates that FDA may conclude additional animal testing or 
clinical assessment is necessary, see sections 10, ``Animal Testing,'' 
and 11, ``Clinical Studies.''
    (Comment 7) A comment said that FDA has failed to fully identify 
the risks to health presented by these devices. A comment said that FDA 
unduly relied upon Medical Device Reports (MDRs) to identify the risks 
to health and that the MDR system is inadequate to fully identify the 
risks. A comment said that risks not identified include pain, stinging, 
or burning upon application, delayed wound healing or tissue toxicity, 
patients picking off the adhesive, and necrosis.
    All of these effects are intrinsic to the risk of adverse tissue 
reaction and chemical burns except for patient ``picking off 
adhesive.'' Although foreseeable, it is not intended for patients to 
``pick off'' the adhesive and therefore is not considered a risk to 
health associated with the intended or otherwise correct use of the 
device. A comment further said that the risks identified by FDA are not 
supported by valid scientific evidence because they are developed from 
the MDR system.
    (Repsonse) FDA disagrees with this comment. FDA believes that it 
has fully identified the significant risks to health presented by these 
devices. As noted in the proposal, FDA did not rely solely upon the MDR 
reports to identify the risks to health presented by these devices. FDA 
also considered the information presented in the petition, 
presentations at the panel meeting, and the panel recommendation.
    (Comment 8) A comment also said that the proposed special controls 
are inadequate to eliminate or mitigate the risks associated with 
tissue adhesives. A comment also said that FDA did not present 
sufficient valid scientific evidence to support the proposed special 
controls because almost half of the articles relate to a single device 
and, therefore, cannot support reclassification of a generic type of 
device.
    (Response) FDA disagrees with the comment. FDA believes that a 
premarket notification that adequately addresses the recommendations of 
the special control guidance and adherence to the general controls of 
the act will mitigate the risks to health associated with these devices 
and provide reasonable assurance of the safety and effectiveness of the 
device. In the premarket notification review process, FDA will assure 
that the device intended for marketing is at least as safe and 
effective as the legally marketed predicate device. FDA believes that 
there is adequate valid scientific evidence on the record about all 
legally marketed tissue adhesives to establish and reclassify a generic 
type of device. Although many of the articles relate to a single 
device, there is substantial evidence concerning other marketed devices 
and that evidence, as well as the remainder of the evidence on the 
record, provides adequate valid scientific evidence to reclassify a 
generic type of device.
    (Comment 9) One comment stated that bench testing as described in 
the special controls guidance document is more informative and 
introduces fewer variables than do animal or clinical studies in 
evaluating these devices.
    (Response) FDA agrees, in general, that animal studies and clinical 
trials for these devices may not be the most appropriate means to 
evaluate these devices. FDA intends to request animal or clinical data 
only when appropriate.
    (Comment 10) One comment asked whether the device is subject to 
current good manufacturing practices (CGMPs).
    (Response) When the device is reclassified into class II, it 
remains subject to the requirements of good manufacturing practices 
(GMPs) under the Quality System Regulation in part 820 (21 CFR part 
820). For more information on the scope of applicability of the Quality 
System Regulation, please see Sec.  820.1, Scope.
    (Comment 11) One comment said the bench testing using American 
Society for Testing and Materials (ASTM) methods described in the 
guidance does not correlate to device performance in the clinical 
setting because the ASTM methods do not include acceptance criteria.
    (Response) Although FDA agrees these methods do not include 
acceptance criteria, FDA disagrees with the premise that these methods 
are inadequate. The methods described in these standards allow direct 
comparison of performance characteristics between devices. For those 
devices where the data demonstrate equivalent performance 
characteristics, no additional clinical testing would be necessary. 
Where the performance characteristics are shown by bench testing to be 
sufficiently different from those of currently legally marketed 
devices, the special controls guidance document indicates that FDA may 
conclude additional animal testing or clinical assessment is necessary. 
See sections 10. Animal Testing and 11. Clinical Studies.
    (Comment 12) One comment suggested that heat of polymerization 
studies recommended in the guidance are not appropriate for materials 
that cure by non-exothermic mechanisms. The second part of the comment 
said that FDA should set an upper limit on the amount of heat generated 
by exothermic mechanisms because of the possibility of burns.
    (Response) FDA agrees, in part, with this comment. Heat of 
polymerization studies are not appropriate methods for evaluating the 
performance characteristics of materials that cure by non-exothermic 
mechanisms. As stated in section 5 of the special controls guidance 
document, a manufacturer proposing to use materials that cure by non-
exothermic mechanisms will need to identify the risks specific to those 
devices by conducting a risk analysis and will need to address the 
risks identified. FDA disagrees with the second part of the comment. 
FDA has set no upper threshold for the heat of polymerization because 
FDA believes the unique properties of each material approved to date 
require a case-by-case evaluation of the heat generated by 
polymerization. Addressing this property is intrinsic to addressing the 
risk of chemical burns, which is one of the risks to health identified 
in the special controls guidance document.
    (Comment 13) One comment said that testing the applicator based on 
the force to express and that moisture vapor transmission testing are 
not relevant. The comment also suggested that, depending on the design 
of the applicator and its components, applicator functionality may be a 
more relevant test.
    (Response) FDA agrees and has revised the guidance accordingly.
    (Comment 14) A comment said that clinical trials are necessary to 
effectively evaluate critical performance parameters. One comment said 
that the record fails to reveal any new valid

[[Page 31031]]

scientific evidence that demonstrates a diminished need for clinical 
testing.
    (Response) FDA generally disagrees with the comment. In accordance 
with the ``least burdensome'' provision of section 513(i)(1)(D) of the 
act, FDA believes that the special controls guidance document 
recommends the submission of the minimum information that is necessary 
to making substantial equivalence determinations. In some cases, 
submission of reports from bench and animal testing and conformance to 
designated standards may be sufficient to demonstrate substantial 
equivalence. FDA also states in the special controls guidance that it 
may recommend the submission of clinical evidence in a premarket 
notification if the proposed device is dissimilar to the legally 
marketed predicate device in material formulation, technology, or 
intended use.
    FDA believes that new information 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 newly available regulatory authority (see Bell v. Goddard, 
supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762 F.Supp. 382, 389-91 
(D.D.C. 1991)), or in light of changes in ``medical science.'' (See 
Upjohn v. Finch, supra, 422 F.2d at 951.) FDA believes that the 
information in the reclassification petition together with information 
presented at the panel meeting and the history of use of the device as 
known to the panel and FDA is sufficient new information to justify the 
reclassification.
    (Comment 15) One comment said that the premarket notification and 
GMP requirements will not provide reasonable assurance of the safety 
and effectiveness of these devices. The comment said that there is no 
coherent generic type of device that would permit meaningful 
substantial equivalence comparisons and determinations. The comment 
also said the premarket notification review process does not afford the 
same level of manufacturing review as the premarket approval process.
    (Response) FDA disagrees with this comment. FDA believes that the 
premarket notification process, in conjunction with the special 
controls guidance document and the general controls of the act, 
including the GMP requirements, will provide reasonable assurance of 
the safety and effectiveness of the device. A manufacturer will need to 
show in a premarket notification that the device it intends to market 
is at least as safe and effective as a legally marketed predicate 
device. This provides a device to which meaningful comparisons can be 
made. While the premarket notification review process does not include 
a pre-clearance GMP inspection, manufacturers of new tissue adhesive 
devices will still be required to be in compliance with the GMP 
requirements at all times.
    (Comment 16) One comment noted that tissue adhesives have been 
considered significant risk devices under the investigational device 
exemption rule (21 CFR 812.3(m)). The comment expressed concern that 
reclassification into class II would result in these devices being 
considered non-significant risk devices and expose patients in studies 
involving newly developed tissue adhesives to risks without adequate 
protection.
    (Response) Reclassification of these devices into class II is not 
inconsistent with the designation of these devices as significant risk 
devices under the investigational device exemption regulations. In the 
special controls guidance document, FDA states: ``If a clinical study 
is needed to demonstrate substantial equivalence (i.e., conducted prior 
to obtaining 510(k) clearance of the device), the study must be 
conducted under the Investigational Device Exemptions (IDE) regulation, 
21 CFR Part 812. FDA generally believes that this device is a 
significant risk device as defined in 21 CFR 812.3(m). In addition to 
the requirement of having an FDA-approved IDE, sponsors of such trials 
must comply with the regulations governing institutional review boards 
(21 CFR Part 56) and informed consent (21 CFR Part 50).''


VI. Risks to Health

    After considering the information in the petition, the information 
presented at the Panel meeting, the Panel's recommendation, and MDRs, 
FDA has evaluated the risks to health associated with use of the tissue 
adhesive for the topical approximation of skin and determined that the 
following risks to health are associated with its use.

A. Unintentional Bonding or Product Leaks into Eyes

    Without adequate protection of the patient's eye, the adhesive may 
inadvertently leak onto the eyelids when tissue adhesive is used on the 
skin near the patient's eye, for example on the brow or forehead. If 
this occurs, this can lead to sealing the eyelids shut and can require 
surgical intervention to remove the adhesive and any bound skin.

B. Wound Dehiscence

    Wound dehiscence, the subsequent separation of the edges of the 
wound, i.e., incision or laceration, during recovery is a risk of all 
surgical procedures and treatments of traumatic wounds. Complications, 
which include re-sealing the wound and surgical revision of the wound 
with adhesive or sutures, can arise as a result of wound dehiscence. 
These complications have the potential to delay the patient's recovery.

C. Adverse Tissue Reaction and Chemical Burns

    Tissue adhesive may be associated with adverse tissue reactions, 
including allergy, inflammation, foreign body reactions, erythema 
(redness), granuloma, and the exacerbation of asthma. In addition, 
fumes given off by the adhesive before or during polymerization can 
cause chemical burns.

D. Infection

    Infection of the skin or soft tissue is a risk to health associated 
with all surgical procedures and wound treatment. If the tissue 
adhesive is not properly sterilized, it may contribute to an increased 
risk of infection.

E. Applicator Malfunction

    Inadequate packaging of the device or user error when opening the 
packaging can result in damage to the applicator and subsequent 
malfunction. If an applicator malfunctions, surgery may be extended, 
resulting in additional time under anesthesia, or treatment may be 
delayed. In addition, if the adhesive is packaged in a glass container, 
lacerations to the user or the patient may result if the glass breaks.

F. Delayed Polymerization

    Polymerization of the adhesive may be delayed, resulting in 
compromise of the wound, additional time under anesthesia, or delayed 
treatment.

[[Page 31032]]

VII. Summary of the Reasons for the Reclassification

    FDA believes that a tissue adhesive for the topical approximation 
of skin should be reclassified into class II because special controls, 
in addition to general controls, would provide reasonable assurance of 
the safety and effectiveness of the device. FDA believes there is 
sufficient information to establish special controls to provide such 
assurance. In addition to the potential risks to health associated with 
use of a tissue adhesive for the topical skin approximation described 
in section V of this document, there is reasonable knowledge of the 
benefits of the device. Specifically, the tissue adhesive for the 
topical approximation of skin may prevent extended bleeding in the 
repair of surgical incisions and traumatic lacerations, promote healing 
of approximated wound edges, and reduce pain and recovery time.

VIII. Special Controls

    In addition to general controls, FDA believes that the guidance 
document entitled ``Class II Special Controls Guidance Document: Tissue 
Adhesive for the Topical Approximation of Skin'' (the class II special 
controls guidance document) is a special control adequate to address 
the risks to health associated with the use of the device described in 
section V of this document. FDA believes that the class II special 
controls guidance document, which incorporates voluntary consensus 
standards and describes labeling recommendations, in addition to 
general controls, provides reasonable assurance of the safety and 
effectiveness of the device. Elsewhere in this issue of the Federal 
Register, FDA is publishing a notice of availability of the class II 
special controls guidance document that is the special control for this 
device.
    The class II special controls guidance document sets forth the 
information FDA believes should be included in premarket notification 
submissions (510(k)s) for the tissue adhesive for the topical 
approximation of skin. FDA has identified the risks to health 
associated with the use of the device in the first column of table 1 of 
this document and the recommended mitigation measures identified in the 
class II special controls guidance document in the second column of 
table 1. FDA believes that addressing these risks to health in a 510(k) 
in the manner identified in the class II special controls guidance 
document, or in an acceptable alternative manner, is necessary to 
provide reasonable assurance of the safety and effectiveness of the 
device.

            Table 1.--Risks to Health and Mitigation Measures
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            Identified Risk              Recommended Mitigation Measures
------------------------------------------------------------------------
Unintentional bonding or product leaks   Bench testing
 into eyes                               Labeling
------------------------------------------------------------------------
Wound dehiscence                         Bench testing
                                         Shelf-life testing
                                         Animal testing
                                         Labeling
------------------------------------------------------------------------
Adverse tissue reaction and chemical     Biocompatibility
 burns                                   Animal testing
------------------------------------------------------------------------
Infection                                Bench testing
                                         Sterility
------------------------------------------------------------------------
Applicator malfunction                   Bench testing
------------------------------------------------------------------------
Delayed polymerization                   Bench testing
                                         Animal testing
------------------------------------------------------------------------

IX. FDA's Findings

    As discussed previously in this document, FDA believes the tissue 
adhesive for the topical approximation of skin can 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 because there is sufficient information to establish special 
controls to provide such assurance. FDA, therefore, is reclassifying 
the device into class II and establishing the draft class II special 
controls guidance document as a special control for the device. Tissue 
adhesives for non-topical use will remain in class III and continue to 
require PMAs.
    Section 510(m) of the act (21 U.S.C. 360) provides that a class II 
device may be exempted from the premarket notification requirements 
under section 510(k) of the act, if the agency determines that 
premarket notification is not necessary to provide reasonable assurance 
of the safety and effectiveness of the device. For this device, for the 
reasons discussed previously, FDA believes that premarket notification 
is necessary to provide reasonable assurance of safety and 
effectiveness and, therefore, does not intend to exempt the device from 
the premarket notification requirements.

X. 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.

XI. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866, 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 final rule is not a significant regulatory action 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

[[Page 31033]]

entities. Reclassification of this device when it is used for the 
topical approximation of skin, from class III to class II, will relieve 
manufacturers of the device of the cost of complying with the premarket 
approval requirements in section 515 of the act (21 U.S.C. 360e). 
Because reclassification will reduce regulatory costs with respect to 
this device, the agency certifies that the 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 
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 $127 million, using the most current (2006) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
rule to result in any 1-year expenditure that would meet or exceed this 
amount.

XII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that 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 has concluded 
that the 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.

XIII. Paperwork Reduction Act of 1995

    This final rule contains no collections of information. Therefore, 
clearance by the Office of Management and Budget (OMB) under the 
Paperwork Reduction Act of 1995 is not required. Elsewhere in this 
issue of the Federal Register, FDA is issuing a notice announcing the 
guidance for the final rule. This guidance, ``Class II Special Controls 
Guidance Document: Tissue Adhesive for the Topical Approximation of 
Skin,'' references previously approved collections of information found 
in FDA regulations.

XIV. References

    The following references have been placed on display in the 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville, MD 20852 and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday.
    1. Regulatory & Clinical Research Institute, Inc. (RCRI), 
reclassification petition, Docket No. 2006P-0071, Minneapolis, MN, 
February 9, 2006.
    2. Regulatory & Clinical Research Institute, Inc., 
reclassification petition, Docket No. 2006P-0071, Minneapolis, MN, 
May 15, 2006.
    3. Regulatory & Clinical Research Institute, Inc., 
reclassification petition, Docket No. 2006P-0071, Minneapolis, MN, 
July 18, 2006.
    4. General and Plastic Surgery Devices Panel, transcript, pp. 
199 to 207, August 25, 2006.

List of Subjects in 21 CFR Part 878

    Medical devices.

0
Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, 21 CFR part 
878 is amended as follows:

PART 878--GENERAL AND PLASTIC SURGERY DEVICES

0
1. The authority citation for 21 CFR part 878 continues to read as 
follows:

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

0
2. Section 878.4010 is added to subpart E to read as follows:


Sec.  878.4010  Tissue adhesive.

    (a) Tissue adhesive for the topical approximation of skin--(1) 
Identification. A tissue adhesive for the topical approximation of skin 
is a device intended for topical closure of surgical incisions, 
including laparoscopic incisions, and simple traumatic lacerations that 
have easily approximated skin edges. Tissue adhesives for the topical 
approximation of skin may be used in conjunction with, but not in place 
of, deep dermal stitches.
    (2) Classification. Class II (special controls). The special 
control for this device is FDA's ``Class II Special Controls Guidance 
Document: ``Tissue Adhesive for the Topical Approximation of Skin.'' 
See Sec.  878.1(e) of this chapter for the availability of this 
guidance document.
    (b) Tissue adhesive for non-topical use--(1) Identification. A 
tissue adhesive for non-topical use, including adhesives intended for 
use in the embolization of brain arteriovenous malformation or for use 
in ophthalmic surgery, is a device used foradhesion of internal tissues 
and vessels.
    (2) Classification. Class III (premarket approval). As of May 28, 
1976, an approval under section 515 of the act is required before this 
device may be commercially distributed. See Sec.  878.3 of this 
chapter.

    Dated: May 21, 2008.
Daniel G. Schultz,
Center for Devices and Radiological Health.
[FR Doc. E8-12078 Filed 5-29-08; 8:45 am]
BILLING CODE 4160-01-S