[Federal Register Volume 81, Number 2 (Tuesday, January 5, 2016)]
[Rules and Regulations]
[Pages 354-361]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-33165]



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Vol. 81

Tuesday,

No. 2

January 5, 2016

Part III





Department of Health and Human Services





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Food and Drug Administration





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21 CFR Part 884





 Obstetrical and Gynecological Devices; Reclassification of Surgical 
Mesh for Transvaginal Pelvic Organ Prolapse Repair; Final Rule

  Federal Register / Vol. 81 , No. 2 / Tuesday, January 5, 2016 / Rules 
and Regulations  

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 884

[Docket No. FDA-2014-N-0297]


Obstetrical and Gynecological Devices; Reclassification of 
Surgical Mesh for Transvaginal Pelvic Organ Prolapse Repair

AGENCY: Food and Drug Administration, HHS.

ACTION: Final order.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
issuing a final order to reclassify surgical mesh for transvaginal 
pelvic organ prolapse (POP) repair from class II to class III. FDA is 
reclassifying these devices based on the determination that general 
controls and special controls together are not sufficient to provide 
reasonable assurance of safety and effectiveness for this device, and 
these devices present a potential unreasonable risk of illness or 
injury. The Agency is reclassifying surgical mesh for transvaginal POP 
repair on its own initiative based on new information.

DATES: This order is effective on January 5, 2016.

FOR FURTHER INFORMATION CONTACT: Sharon Andrews, Center for Devices and 
Radiological Health, 10903 New Hampshire Ave., Bldg. 66, Rm. G110, 
Silver Spring, MD 20993, 301-796-6529, [email protected].

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as 
amended, 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(d) of the FD&C Act, devices that were in 
commercial distribution before the enactment of the 1976 amendments, 
May 28, 1976 (generally referred to as preamendments devices), are 
classified after FDA has: (1) Received a recommendation from a device 
classification panel (an FDA advisory committee); (2) published the 
panel's recommendation for comment, along with a proposed regulation 
classifying the device; and (3) published a final regulation 
classifying the device. FDA has classified most preamendments devices 
under these procedures.
    Devices that were not in commercial distribution prior to May 28, 
1976 (generally referred to as postamendments devices), are 
automatically classified by section 513(f) of the FD&C Act into class 
III without any FDA rulemaking process. Those devices remain in class 
III and require premarket approval unless, and until, the device is 
reclassified into class I or II or FDA issues an order finding the 
device to be substantially equivalent, in accordance with section 
513(i) of the FD&C Act, to a predicate device that does not require 
premarket approval. The Agency determines whether new devices are 
substantially equivalent to predicate devices by means of premarket 
notification procedures in section 510(k) of the FD&C Act (21 U.S.C. 
360(k)) and 21 CFR part 807.
    On July 9, 2012, the Food and Drug Administration Safety and 
Innovation Act (FDASIA) (Pub. L. 112-144) was enacted. Section 608(a) 
of FDASIA amended section 513(e) of the FD&C Act, changing the 
mechanism for reclassifying a device from rulemaking to an 
administrative order. Section 513(e) of the FD&C Act provides that FDA 
may, by administrative order, reclassify a device 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 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 
Co. 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 action where the reevaluation is made 
in light of newly available authority (see Bell, 366 F.2d at 181; 
Ethicon, Inc. v. FDA, 762 F.Supp. 382, 388-391 (D.D.C. 1991)), or in 
light of changes in ``medical science'' (Upjohn, 422 F.2d at 951). 
Whether data before the Agency are old 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., Gen. Medical Co. v. FDA, 
770 F.2d 214 (D.C. Cir. 1985); Contact Lens Mfrs. Assoc. v. FDA, 766 
F.2d 592 (D.C. Cir. 1985), cert. denied, 474 U.S. 1062 (1986).)
    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 513(e)(1) of the FD&C Act sets forth the process for 
issuing a final reclassification 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 to a public docket.
    FDA published a proposed order (the 513(e) proposed order) to 
reclassify this device in the Federal Register of May 1, 2014 (79 FR 
24634). FDA received and has considered approximately 200 comments on 
this 513(e) proposed order, as discussed in section II.
    FDA held a meeting on September 8 and 9, 2011 (76 FR 41507, July 
14, 2011) of the Obstetrics and Gynecology Devices Panel of the Medical 
Devices Advisory Committee (``the Panel''), a device classification 
panel described in section 513(b) of the FD&C Act, to discuss whether 
surgical mesh for transvaginal POP repair should be reclassified into 
class III or remain in class II (Ref. 1). The Panel discussed a number 
of serious adverse events associated with use of surgical mesh for 
transvaginal POP repair. The Panel consensus was that the safety of 
surgical mesh for transvaginal POP repair is not well established and 
that, depending on the compartment, placement of surgical mesh for 
transvaginal POP repair may not be more effective than traditional 
``native-tissue'' repair without mesh. As such, the Panel concluded 
that the risk-benefit profile of surgical mesh for transvaginal POP 
repair is not well established. The Panel consensus was that general 
controls and special controls together would not be sufficient to 
provide reasonable assurance of the safety and effectiveness of 
surgical mesh for transvaginal POP repair, and that these devices 
should be reclassified from class II to class III (Ref. 1). FDA is not 
aware of new information since the

[[Page 355]]

Panel meeting that would provide a basis for a different recommendation 
or findings.
    In the 513(e) proposed order, FDA also proposed to reclassify 
surgical instrumentation for urogynecologic surgical mesh procedures 
from class I to class II and establish special controls. FDA is not 
finalizing the proposed reclassification and special controls for 
surgical instrumentation for use with urogynecologic surgical mesh at 
this time. As stated in the 513(e) proposed order preamble, FDA will 
convene a panel to discuss specialized surgical instrumentation for use 
with urogynecologic surgical mesh prior to finalizing reclassification 
of instrumentation for this use. On February 26, 2016, the 
Gastroenterology and Urology Devices Panel of the Medical Devices 
Advisory Committee will have a panel meeting to discuss and make 
recommendations for reclassification of these specialized surgical 
instrumentation devices.

II. Public Comments in Response to the 513(e) Proposed Order

    In response to the 513(e) proposed order to reclassify surgical 
mesh for transvaginal POP repair, FDA received approximately 200 
comments. The comments and FDA's responses to the comments are 
summarized in this section. Certain comments are grouped together under 
a single number because the subject matter of the comments is similar. 
The number assigned to each comment is purely for organizational 
purposes and does not signify the comment's value or importance or the 
order in which it was submitted.
    (Comment 1) Approximately 70 comments were received from 
individuals or family members of individuals who underwent mesh repair 
for POP, stress urinary incontinence (SUI), and/or hernias and reported 
complications or adverse events experienced during or after their 
procedures. The complications and adverse events reported included 
organ perforation, bleeding, chronic pain, mesh exposure or extrusion 
into the vagina and/or visceral organs (in some cases requiring 
additional surgery), infection, atypical vaginal discharge, painful 
sexual intercourse, self-catheterization, recurrent prolapse and/or 
incontinence, additional corrective surgery, and other permanent and/or 
life-altering adverse events.
    (Response) FDA appreciates the comments received from individuals 
sharing their experiences following surgical mesh repair for POP, SUI, 
and/or hernias. The complications and adverse events reported by these 
commenters are consistent with those addressed in the 513(e) proposed 
order preamble and discussed at the 2011 Panel meeting. The comments 
did not identify any adverse event information that was not already 
considered by FDA and the Panel.
    (Comment 2) Approximately 50 comments requested reclassification of 
surgical mesh for indications other than transvaginal POP repair, 
including for SUI and hernia.
    (Response) Surgical mesh for indications other than transvaginal 
POP repair is outside the scope of the 513(e) proposed order and this 
document. In the 513(e) proposed order (79 FR 24634 at 24636), FDA 
stated that this proposed order does not include surgical mesh 
indicated for surgical treatment of stress urinary incontinence, 
sacrocolpopexy (transabdominal POP repair), hernia repair, and other 
non-urogynecologic indications.
    (Comment 3) Approximately 50 comments requested a ban, recall, or 
``suspension of use'' of all surgical mesh devices.
    (Response) As stated previously, surgical mesh for indications 
other than transvaginal POP repair is outside the scope of this final 
order. For the reasons discussed in this document, FDA does not believe 
that a ban, recall or suspension of use of surgical mesh for 
transvaginal POP repair is warranted at this time.
    Section 516 of the FD&C Act (21 U.S.C. 360f) authorizes FDA to ban 
a device when, on the basis of all available data and information, FDA 
finds that the device presents substantial deception or an unreasonable 
and substantial risk of illness or injury and, where such deception or 
risk could be corrected or eliminated by labeling or change in labeling 
and with respect to which the Secretary of the Department of Health and 
Human Services (Secretary) provided written notice to the manufacturer 
specifying the deception or risk of illness or injury, the labeling or 
change in labeling to correct the deception or eliminate or reduce such 
risk, and the period within which such labeling or change in labeling 
was to be done, such labeling or change in labeling was not done within 
such period.
    FDA does not believe there is sufficient evidence at this time to 
support the banning of this device. Based on a review of the published 
literature, as described in the 513(e) proposed order preamble and this 
document, input from clinical organizations, and the Panel's 
recommendations, FDA has determined that the safety and effectiveness 
of surgical mesh for transvaginal POP repair has not been established 
and that the collection of additional clinical evidence on these 
devices is needed. Such additional evidence may provide information to 
allow FDA to impose controls to mitigate the risks and more clearly 
characterize the benefits of these devices. In addition, FDA believes 
there are potential benefits from surgical mesh used for transvaginal 
POP repair including treatment of POP in appropriately selected women 
with severe or recurrent prolapse. As such, FDA has not determined that 
this device presents an unreasonable and substantial risk of illness or 
injury.
    FDA also does not believe there is sufficient evidence at this time 
to support a mandatory recall of this device. Under section 518(e) of 
the FD&C Act (21 U.S.C. 360h(e)), if the Secretary finds that there is 
a reasonable probability that a device intended for human use would 
cause serious, adverse health consequences or death, the Secretary 
shall issue an order requiring the appropriate person (including the 
manufacturers, importers, distributors, or retailers of the device) to 
immediately cease distribution of such device, and to immediately 
notify health professionals and device user facilities of the order and 
to instruct such professionals and facilities to cease use of such 
device.
    FDA does not believe a mandatory recall of all currently marketed 
surgical mesh for transvaginal POP repair is warranted. Based on a 
review of the published literature as described in the 513(e) proposed 
order preamble and this document, input from clinical organizations, 
and the Panel's recommendations, FDA believes that there is not 
sufficient evidence at this time to support a finding that there is a 
reasonable probability that surgical mesh for transvaginal repair of 
POP would cause serious adverse health consequences or death. As 
described in the 513(e) proposed order preamble and discussed at the 
2011 Panel meeting, the safety and effectiveness of surgical mesh for 
transvaginal repair of POP has not been established and these devices 
should be evaluated in clinical studies that compare the device to 
native tissue repair in order to establish a reasonable assurance of 
safety and effectiveness.
    It is unclear what commenters were referencing when they asked FDA 
to ``suspend the use'' of these devices. As stated previously, FDA does 
not believe a ban or recall is warranted at this time, and as stated in 
this document, there are other actions FDA has taken and may take in 
the future to ensure that there is

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a reasonable assurance of the safety and effectiveness of surgical mesh 
for transvaginal POP repair.
    FDA believes other regulatory actions it has taken will help the 
Agency to better understand the risk-benefit profile of these devices. 
FDA issued postmarket surveillance orders under section 522 of the FD&C 
Act (21 U.S.C. 360l) to manufacturers of surgical mesh for transvaginal 
POP repair starting on January 3, 2012. The postmarket surveillance 
orders allow FDA to continue to evaluate the benefit-risk profile of 
the device. Further, by reclassifying these devices to class III and 
requiring PMA approval, FDA can require an independent demonstration 
that a reasonable assurance of safety and effectiveness exists for each 
device within this type. Elsewhere in this issue of the Federal 
Register, FDA is issuing a final order under section 515(b) of the FD&C 
Act (21 U.S.C. 360e(b)) (the 515(b) final order) to require the filing 
of a PMA or notice of completion of a product development protocol for 
surgical mesh for transvaginal POP repair. The preamble of the 515(b) 
final order provides further information regarding the data and 
scientific evidence needed for a PMA.
    FDA will consider other regulatory actions relating to this device 
as appropriate in the future.
    (Comment 4) Approximately 20 comments stated that the polypropylene 
material used to fabricate surgical mesh is inappropriate for 
implantation. These comments contend that the degradation of the 
polypropylene mesh in vivo may lead to systemic effects that can cause 
serious complications.
    (Response) FDA believes that a thorough evaluation of the material 
used to fabricate surgical mesh for transvaginal POP repair is needed 
to provide a reasonable assurance of safety and effectiveness of the 
device. The findings set forth in the 515(b) proposed order preamble, 
as discussed in this document, address this issue (these findings are 
adopted, as amended, in the 515(b) final order that is published 
elsewhere in this issue of the Federal Register).
    In the 515(b) proposed order preamble, FDA stated that 
manufacturers should provide information in their PMAs regarding 
biocompatibility, preclinical bench testing and preclinical animal 
studies, among other proposed information, to demonstrate reasonable 
assurance of safety and effectiveness of surgical mesh for transvaginal 
POP repair. Such performance data, which may generally include 
assessment of the mesh chemical and physical characteristics, in vitro 
chemical characterization studies, and in vivo preclinical implantation 
studies, will be reviewed by FDA to determine whether the risks 
associated with implantation of the polypropylene material are 
appropriately mitigated. The 515(b) proposed order preamble also stated 
that a PMA would need to include the information required by section 
515(c)(1) of the FD&C Act, which includes manufacturing information. 
FDA's review of such manufacturing information will allow the Agency to 
evaluate whether the polypropylene material is safe and effective for 
transvaginal POP repair.
    (Comment 5) One comment stated that FDA should not include non-
crosslinked biologic grafts in this reclassification and that such 
grafts should not be subject to postmarket surveillance studies. The 
comment stated that the 513(e) proposed order cited relatively few 
studies that examine the use of biologically derived grafts for POP 
repair. The comment also noted that FDA's analysis did not distinguish 
crosslinked versus non-crosslinked biologic grafts. The comment 
requested that FDA review additional data, including a summary of 18 
publications regarding non-crosslinked biologic grafts submitted by the 
commenter, and consider the different risk profiles of biologic grafts 
and specifically whether non-crosslinked biologic grafts should be 
reclassified.
    (Response) As discussed in the response to comment 9, FDA performed 
an updated review of the literature to consider new clinical 
information available since publication of the 513(e) and 515(b) 
proposed orders and additional publications cited by the commenter, and 
whether non-crosslinked biologic grafts should be reclassified. Based 
on this review, FDA believes that there is currently insufficient 
evidence to support a finding that the benefit-risk profile of non-
crosslinked biologic grafts differs from that of synthetic meshes. 
There is little evidence overall on biologic grafts (as compared to 
synthetic meshes), and the majority of studies evaluating non-
crosslinked biologic grafts are on small populations and are not 
prospective. Moreover, the limited clinical evidence that is available 
indicates that like synthetic surgical mesh for transvaginal POP 
repair, non-crosslinked biologic mesh is associated with adverse events 
and does not demonstrate effectiveness compared to traditional (i.e., 
native tissue) repair of POP.
    The commenter cited 18 publications reporting outcomes for non-
crosslinked biologic graft for use in transvaginal or transabdominal 
POP repair (Refs. 2 through 19). As described in this document, these 
publications in totality do not provide sufficient evidence of the 
reasonable safety and effectiveness of non-crosslinked biologic grafts.
    Of these publications, 6 of the 18 report outcomes on fewer than 15 
study subjects (Refs. 2 through 7). Due to the small sample size, the 
outcomes from these publications are difficult to interpret and FDA 
could not conclude that the risk profiles of non-crosslinked biologic 
grafts were different than synthetic meshes.
    Of the remaining 12 publications, 1 describes outcomes after 
sacrocolpopexy (Ref. 2), 1 describes use of a non-crosslinked biologic 
graft to cover a vaginal wall defect following explantation of a 
synthetic mesh to treat prolapse (Ref. 3), and 1 describes 
transperineal repair of rectocele (Ref. 4). These uses are outside the 
scope of the reclassification.
    One publication reported a retrospective review of non-
contemporaneous mesh-augmented (non-crosslinked biologic and synthetic) 
versus native tissue anterior compartment repair (Ref. 5). One author 
in that report switched to the mesh-augmented technique part way 
through the period covered by the study due to dissatisfaction with 
native tissue repair. This may affect the objectivity of the study 
results and may lead to a conclusion that inappropriately favors mesh-
augmented repair. Anatomic success was greater in mesh-augmented 
patients; however, objective anatomic success was defined as Stage 0 or 
1 using the Baden-Walder system (Stage 0--normal position, Stage 1--
descent halfway to the hymen). This may represent an ideal outcome, but 
does not necessarily represent a clinically relevant outcome. As 
discussed in the 513(e) proposed order preamble, prolapse staging 
systems like the Pelvic Organ Prolapse Quantification (POP-Q) are ``not 
correlated with POP symptoms or patient assessment of improvement 
[(Barber et al., 2009)].''
    Another publication reported long-term followup in a retrospective 
patient cohort (N = 41) who had undergone graft repair of anterior or 
posterior vaginal prolapse compared to a contemporaneous cohort of 
``matched'' native tissue repair controls (Ref. 6). Subjective outcomes 
were significantly better in the graft cohort; however, recurrence 
tended to be greater in the graft cohort when defined strictly as 
>=POP-Q Stage 2. This means that the graft cohort experienced greater 
anatomic failure when using POP-Q

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Stage 1 as the cutoff for anatomic success.
    One publication described a retrospective case review without 
native tissue control (Ref. 7). This review (N = 65) found a subjective 
success (no symptoms and no bulge beyond the hymen) rate of 92 percent. 
Reoperation rate for de novo and recurrent prolapse was 7.7 percent, 
and three women had repeat surgery at the same anatomic site (anterior 
compartment). Because this study did not include a control group, we 
are unable to compare safety and effectiveness outcomes between 
patients who received mesh and patients who underwent native tissue 
repair.
    Two publications described prospective cohorts. In one small series 
(N = 21), women with recurrent prolapse underwent anterior, posterior, 
or combined anterior/posterior repair with non-crosslinked biologic 
mesh (Ref. 8). Mean POP-Q scores preoperatively were Ba = 0.63 versus 
Ba = 1.75 postoperatively. Preoperative Bp score was -0.2 versus Bp -
2.2 postoperatively. The authors reported a mean followup of 29 months. 
Six patients reported persistent bulge, and eight patients reported 
vaginal discomfort. This study has a small sample size and does not 
allow for comparison to native tissue repair.
    The other prospective cohort study (N = 50) evaluated patient-
reported outcomes at 6 months following posterior compartment repair 
augmented with non-crosslinked mesh (Ref. 9). Although significant 
improvements were noted for vaginal symptoms, sexual matters score and 
quality of life on the International Consultation on Incontinence 
Questionnaire vaginal symptoms questionnaire, anatomic outcomes were 
not collected. Therefore, effectiveness outcomes cannot be evaluated 
from this study.
    Only three of the remaining publications described prospective 
randomized controlled trials (RCTs) comparing anterior or posterior 
vaginal repair using non-crosslinked biologic graft versus native 
tissue repair (Refs. 10 through 12). None of the three RCTs defined 
anatomic success as the leading edge of prolapse at or above the 
hymenal ring, which is considered a more clinically relevant outcome 
compared to POP-Q score. The criterion for anatomic success of prolapse 
repair in the American Urogynecologic Society (AUGS) Pelvic Floor 
Disorders Registry is leading edge at or above the hymen (Ref. 13).
    The final publication identified by the commenter described 
prospective followup of a cohort assembled from a retrospective chart 
review (N = 59) (Ref. 14). This report does define anatomic success at 
the hymenal ring. Objective recurrence of prolapse in this study was 
approximately 31 percent.
    Regarding mesh exposure/erosion, the publications cited by the 
commenter suggests that the risk of vaginal exposure/erosion for the 
non-crosslinked mesh is low. In the 513(e) proposed order preamble, FDA 
noted that the incidence of mesh exposure did not differ between 
nonabsorbable synthetic mesh (10.3 percent) and biologic graft material 
(10.1 percent) (Ref. 15).
    For other types of surgical complications, one RCT (N = 56) found 
that the number of complications in the mesh group was greater compared 
to the native tissue repair group (Ref. 10). Blood loss was greater for 
mesh versus native tissue rectocele repair in another RCT (N = 160) 
(Ref. 12). In the same RCT, there was a trend towards increased risk of 
wound separation following non-crosslinked graft repair versus native 
tissue repair; however, the outcome did not reach statistical 
significance.
    In addition, serious adverse events are reported in association 
with non-crosslinked biologic graft, including pain necessitating 
resurgery (Ref. 14). In this study, surgical complications included 
cystotomy (6.8 percent) and enterotomy (1.7 percent). Twenty-four 
percent of subjects had postoperative voiding dysfunction, and there 
was a 5.1 percent rate of hemorrhage requiring transfusion. (It is 
unclear whether these complications were device-related). The rate of 
dyspareunia at followup was 8.3 percent. The study did not include a 
control group, so it is unknown how the benefits and risks of graft-
augmented repair with the non-crosslinked biologic graft would have 
compared with a native tissue repair.
    In summary, there is insufficient available evidence from 
prospective studies using an appropriate primary endpoint for anatomic 
success on which to evaluate the effectiveness of transvaginal POP 
repair using non-crosslinked biologic mesh versus native tissue repair. 
The available clinical outcomes provide evidence that non-crosslinked 
biologic mesh is associated with adverse events. There are no data from 
RCTs with long-term followup that demonstrate clinical effectiveness of 
this material for transvaginal POP repair compared to native tissue 
repair.
    As a result of these findings, FDA is not differentiating between 
non-crosslinked biologic grafts and synthetic mesh for transvaginal POP 
repair in this reclassification order and is reclassifying all of these 
devices from class II to class III. FDA's decision is in line with the 
2011 Panel, which did not recommend stratification of surgical mesh for 
transvaginal POP repair by material characteristics.
    (Comment 6) Approximately 20 comments stated that patients were not 
adequately informed of the possible complications following mesh 
implantation or that patients were not informed prior to surgery that 
mesh would be implanted.
    (Response) FDA believes that patients should be adequately informed 
regarding the possible complications associated with surgical mesh. As 
stated in the FDA Safety Communication published in July 2011 (Ref. 
16), health care providers should: (1) Inform patients that 
implantation of surgical mesh is permanent and that some complications 
associated with the implanted mesh may require additional surgery that 
may or may not correct the complication; (2) inform patients about the 
potential for serious complications and their effect on quality of 
life, including pain during sexual intercourse, scarring, and narrowing 
of the vaginal wall in POP repair using surgical mesh; and (3) provide 
patients with a copy of the patient labeling from the surgical mesh 
manufacturer, if available. The 2011 Safety Communication also includes 
recommendations for patients to help them obtain the appropriate 
information prior to a surgical mesh repair.
    The Panel recommended that FDA focus on development of patient 
labeling and provide patients with benefit-risk information on 
available treatment options for POP, including surgical and nonsurgical 
options, to help patients understand long-term safety and effectiveness 
outcomes (Ref. 1, p. 150).
    For these reasons, in the findings of the 515(b) proposed order, 
which are adopted as amended in the 515(b) final order that is being 
published elsewhere in this issue of the Federal Register, FDA asserted 
that manufacturers should include in their PMAs for these devices 
professional and patient labeling, and that the patient labeling would 
be expected to include, among other things, the risks and benefits of 
the device and available treatment options. Therefore, it is expected 
that PMAs for these devices include professional and patient labeling, 
and that the patient labeling include, among other things, the risks 
and benefits of the device and available treatment options.
    (Comment 7) Approximately 30 comments stated that surgical mesh 
should be adequately tested, including

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rigorous clinical evaluation prior to marketing. Comments also 
emphasized the need to understand the long-term effects of surgical 
mesh.
    (Response) FDA agrees that surgical mesh for transvaginal POP 
repair should be adequately tested prior to marketing to provide a 
reasonable assurance of safety and effectiveness. FDA believes that 
surgical mesh for transvaginal POP repair should undergo mechanical and 
chemical characterization and performance evaluation, biocompatibility, 
sterilization validation, shelf life, and preclinical in vivo testing 
to provide a reasonable assurance of safety and effectiveness of the 
device prior to marketing. In addition, surgical mesh for transvaginal 
POP repair should be evaluated clinically, specifically to evaluate the 
safety and effectiveness of the device compared to native tissue 
repair. In the 515(b) final order that is being published elsewhere in 
this issue of the Federal Register, FDA is requesting that 
manufacturers provide this information to support premarket approval of 
surgical mesh for transvaginal POP repair.
    With respect to long-term effects of surgical mesh, FDA believes 
that the clinical evaluation of surgical mesh for transvaginal POP 
repair should include long-term followup. FDA issued postmarket 
surveillance orders under section 522 of the FD&C Act for these devices 
that will collect long-term followup out to 3 years post implantation.
    The comments also referenced surgical mesh for SUI and 
sacrocolpopexy. As stated previously, surgical mesh for indications 
other than transvaginal repair of POP is outside the scope of this 
final order.
    (Comment 8) Approximately five comments stated the mesh for 
treatment of female SUI and sacrocolpopexy should not be reclassified 
to class III.
    (Response) As stated previously, surgical mesh for indications 
other than transvaginal POP repair are outside the scope of this final 
order.
    (Comment 9) One comment stated that FDA should evaluate recent data 
on POP mesh repair as the recent literature is more representative of 
current technologies, instructions for use, and physician training of 
currently marketed devices and that erosion rates and complication 
rates are lower in current literature than compared to rates cited in 
the 513(e) proposed order.
    (Response) FDA conducted an updated review of the literature 
published since the 513(e) and 515(b) proposed orders were issued and 
reviewed additional publications cited by the commenter, summarized in 
further detail in this document, and determined that the weight of the 
evidence indicates that use of surgical mesh for transvaginal POP 
repair is not strongly or consistently associated with increased 
benefits over native tissue repair in the treatment of stage 2 or 
higher POP. Overall, the evidence indicates that mesh surgeries take 
longer to perform, result in greater blood loss, and have a 
considerable risk of postoperative mesh erosion in comparison to native 
tissue repair. In addition, there is suggestive evidence that use of 
surgical mesh for transvaginal POP repair may pose a higher risk of de 
novo POP relative to native tissue repair.
    The majority of studies identified by the commenter, and considered 
in the updated literature review conducted by FDA, assessed the 
anterior compartment; therefore, it is difficult to draw conclusions on 
the differential effects of mesh by compartment, relative to native 
tissue repair. Furthermore, data from prospective, randomized studies 
comparing surgical mesh and native tissue repair using a clinically 
relevant definition of success are limited at this time. The benefit-
risk profile comparison favors native tissue repair over use of 
surgical mesh for transvaginal POP repair. FDA concludes that the 
updated literature review further supports the reclassification of 
surgical mesh for transvaginal POP repair from class II to class III as 
reasonable assurance of safety and effectiveness for the device has not 
been demonstrated.
    The comment stated that four recent systematic reviews on surgical 
options for POP continue to support use of transvaginal mesh to treat 
anterior wall prolapse (Refs. 17 through 20). One of these systematic 
reviews was cited in the 513(e) proposed order preamble (Ref. 19) and 
therefore is not discussed in detail here. This systematic review 
evaluated surgical management of POP in women and concluded that ``The 
use of grafts (biological or synthetic) reduces the risk of prolapse 
symptoms and recurrent anterior vaginal prolapse on examination when 
compared to native tissue repairs (colporrhaphy). However, the 
advantages of a permanent polypropylene mesh must be weighed against 
disadvantages including longer operating time, greater blood loss, 
prolapse in other areas of the vagina, new onset urinary stress 
incontinence, and the mesh becoming exposed in the vagina in 11 percent 
of women. In general, there is a lack of evidence to support 
transvaginal mesh operations used in apical or posterior compartment 
surgery.'' The second of these two reviews reported on anterior vaginal 
compartment repair specifically (Ref. 18). The review specific to 
anterior vaginal compartment repair noted that improved anatomic 
outcomes conferred by surgical mesh used for anterior POP repair are 
not always accompanied by improvement in subjective outcomes. Whereas 
polypropylene mesh appears to lead to improvement in both anatomic and 
subjective outcomes, these results did not lead to improved functional 
outcomes using validated questionnaires or to a lower reoperation rate 
for POP. This review concluded that surgical mesh is significantly 
associated with longer operating time, greater blood loss, and 
development of POP in another vaginal compartment. The author also 
noted a nonsignificant tendency towards higher cystotomy, de novo 
dyspareunia, and de novo SUI rate compared to native tissue anterior 
repair.
    The third systematic review cited by the commenter was to address 
nonsurgical treatments for POP, effects of POP surgery by vaginal 
compartment, and how different mesh materials affect surgical repair of 
POP (Ref. 17). Regarding anterior prolapse repair with mesh, the author 
did not reach a conclusion regarding the need for reoperation for POP 
or SUI following index POP surgery; however, anterior repair using 
surgical mesh was found to increase risk for revision of the vaginal 
wound due to mesh exposure.
    The focus of the fourth systematic review cited by the commenter 
described complications following POP repair using surgical mesh (Ref. 
20). The review found that the mean total complication rate in the 
anterior compartment was 27 percent and that there was an 8 percent 
rate of complications >= grade III on the Clavien-Dindo classification 
system (i.e., requiring surgical, endoscopic, or radiological 
intervention).
    The comment also stated that these recent systematic reviews report 
complication rates that required surgical intervention ranging from 6.3 
to 9 percent in the anterior compartment versus the ``upper bound of 22 
percent cited in the proposed order.'' In the 513(e) proposed order 
preamble, FDA stated the following: ``From the one RCT that directly 
compared sacrocolpopexy to transvaginal POP repair with mesh (both 
using synthetic nonabsorbable mesh), overall re-surgery within 2 years 
postoperative was significantly more common following transvaginal POP 
repair with mesh than laparoscopic sacrocolpopexy, with rates of 22 
percent (12/55) and 5 percent (3/53),

[[Page 359]]

respectively (p = 0.006) (79 FR 24637).'' The 22 percent cited by FDA 
in the 513(e) proposed order preamble was not specific for anterior 
repair, but rather included all vaginal compartments.
    In addition to the four recent systematic reviews discussed 
previously, the commenter cited 43 published reports, of which 31 are 
abstracts or poster presentations. Based on the limited scientific 
evidence in these abstracts and poster presentations, they are 
difficult to evaluate, and therefore, FDA was unable to draw any 
conclusions from these publications. The comment stated that 
collectively, the studies report mesh exposure rates of 0 to 8 percent 
and of the mesh exposures, only approximately 38 percent required 
surgical intervention. The comment stated this outcome represents a 
reduction compared to the 7.2 percent rate cited in the 513(e) proposed 
order. However, the 7.2 percent rate cited by FDA in the 513(e) 
proposed order preamble was the rate of reoperation due to any 
complication, and not specifically for mesh exposure-related 
complications.
    The comment also stated that the more recent literature defines 
success as improved anatomic and subjective outcomes compared to native 
tissue repair. Of the publications that were not abstracts or posters, 
there is only one in which surgical mesh repair was compared to native 
tissue (Ref. 21). In that study, the primary outcome was ideal anatomic 
support based on POP-Q stage, and not subjective outcomes. Anatomic 
success, defined as POP-Q stage 0 or 1 was greater for the surgical 
mesh repair in the anterior compartment; however, improvement in 
quality of life was not statistically significant between groups. In 
addition, subjects in the surgical mesh group had statistically 
significant longer hospital stays, operative time, and estimated blood 
loss.
    With one exception, of the publications cited by the commenter to 
represent success rates for one line of mesh products, the definition 
of a success was ideal anatomic support (Refs. 22 through 27). As noted 
in the 513(e) proposed order preamble, ideal anatomic support is not a 
prerequisite for improvement in patient symptoms. As stated previously 
in this document, the anatomic criterion for success following surgical 
repair of prolapse in the AUGS Pelvic Floor Disorders Registry is 
absence of leading edge of prolapse beyond the hymen, not POP-Q Stage 
<= 1. In addition, because these studies did not compare outcomes 
between mesh repair and native tissue repair, it is unknown whether the 
success among mesh subjects would have exceeded that of native tissue 
repair.
    One publication that evaluated more clinical and/or subjective 
outcomes compared two mesh products (Ref. 26). The failure of the mesh 
repair ranged from 24 percent to 46 percent, depending on the outcome 
measure. Mesh exposure occurred at a rate of 8 percent. Pelvic pain was 
reported at 7.4 percent, and of study subjects who were sexually 
active, 12.7 percent reported painful intercourse. In one prospective 
study (N = 30), no anatomic outcomes were reported; however, the report 
stated that no patients had symptoms of recurrent prolapse at 12 months 
of followup. Two patients in this cohort had mesh erosion which 
required partial mesh excision (Ref. 28).
    The remaining publications cited in the comment address mesh 
exposure, mesh repair as an ambulatory procedure, and stability of an 
anchor device used to attach the mesh to an anatomic target (Refs. 29 
through 31). The rate of mesh exposure in the first study was 8.1 
percent (Ref. 28). None of these publications compared mesh repair to 
native tissue repair, nor does any reflect a study designed to evaluate 
surgical success.
    In summary, FDA concludes that the literature published since the 
513(e) and 515(b) proposed orders were issued and the additional 
literature cited by the commenter further supports the reclassification 
of surgical mesh for transvaginal POP repair from class II to class 
III.
    (Comment 10) One comment noted that direct comparison of safety 
results between sacrocolpopexy, transvaginal repair, and native tissue 
repair can be misleading if the vaginal repair does not have a vaginal 
vault component.
    (Response) Based on the evidence cited in the 513(e) proposed order 
preamble, FDA concluded that the types of risks associated with 
transvaginal mesh for POP repair are similar across different vaginal 
compartments. FDA is unaware of any new evidence that supports the 
conclusion that the types of risk associated with transvaginal mesh for 
POP are different across different vaginal compartments. However, FDA 
acknowledges that the frequency of different types of adverse events 
may vary across different vaginal compartments. FDA's conclusion is in 
line with the Panel, which did not recommend that reclassification be 
stratified by compartment. For the reasons discussed in the 513(e) 
proposed order preamble and in this document, the reclassification 
applies to all transvaginal mesh for POP repair regardless of location 
of repair.
    (Comment 11) One comment stated that the 513(e) proposed order 
makes definitive statements regarding benefit/risk, when in fact 
additional studies are needed to establish benefit/risk.
    (Response) FDA disagrees that the 513(e) proposed order makes 
definitive statements regarding benefit/risk. Throughout the 513(e) 
proposed order preamble, FDA described its conclusions as 
``tentative.''

III. The Final Order

    Under section 513(e) of the FD&C Act, FDA is adopting its findings 
as published in the preamble to the 513(e) proposed order (79 FR 
24634). FDA is issuing this final order to reclassify surgical mesh for 
transvaginal POP repair from class II to class III. FDA is 
reclassifying these devices based on the determination that general 
controls and special controls together are not sufficient to provide 
reasonable assurance of safety and effectiveness for this device. In 
addition, in the absence of an established positive benefit-risk 
profile, FDA has determined that the risks to health associated with 
the use of surgical mesh for transvaginal POP repair identified 
previously present a potential unreasonable risk of illness or injury.
    FDA has modified the proposed identification in Sec.  884.5980(a) 
for surgical mesh for transvaginal pelvic organ prolapse repair to 
clarify that the materials of construction may include synthetic 
material, non-synthetic material, or a combination of synthetic and 
non-synthetic materials.

IV. Analysis of 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.

V. Paperwork Reduction Act of 1995

    This final 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 814, subpart B, have been 
approved under OMB control number 0910-0231; and the collections of 
information under 21 CFR part 801 have been approved under OMB control 
number 0910-0485.

[[Page 360]]

VI. Codification of Orders

    Prior to the amendments by FDASIA, section 513(e) of the FD&C Act 
provided for FDA to issue regulations to reclassify devices. Although 
section 513(e) of the FD&C Act, as amended, requires FDA to issue final 
orders rather than regulations, FDASIA also provides for FDA to revoke 
previously issued regulations by order. FDA will continue to codify 
classifications and reclassifications in the Code of Federal 
Regulations (CFR). Changes resulting from final orders will appear in 
the CFR as changes to codified classification determinations or as 
newly codified orders. Therefore, under section 513(e)(1)(A)(i) of the 
FD&C Act, as amended by FDASIA, in this final order, we are codifying 
the reclassification of surgical mesh for transvaginal POP repair into 
class III in 21 CFR 884.5980.

VII. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852, and are available for viewing by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday; 
they are also available electronically at http://www.regulations.gov. 
FDA has verified the Web site addresses, as of the date this document 
publishes in the Federal Register, but Web sites are subject to change 
over time.

1. Transcript of the September 8 and 9, 2011, Meeting of the 
Obstetrics and Gynecological Devices Panel. Available at http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ObstetricsandGynecologyDevices/UCM275043.pdf and http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ObstetricsandGynecologyDevices/UCM275061.pdf.
2. Deprest, J., D. de Ridder, J.P. Roovers, et al., ``Medium Term 
Outcome of Laparoscopic Sacrocolpopexy With Xenografts Compared to 
Synthetic Grafts.'' Journal of Urology 182: 2362-2368, 2009.
3. Jeffery, S.T . and A. Nieuwoudt, ``Beyond the Complications: 
Medium-Term Anatomical, Sexual and Functional Outcomes Following 
Removal of Trocar-Guided Transvaginal Mesh. A Retrospective Cohort 
Study.'' International Urogynecology Journal 23(10): 1391-1396, 
2012.
4. Ellis, C. N., ``Outcomes After the Repair of Rectoceles With 
Transperineal Insertion of a Bioprosthetic Graft.'' Diseases of the 
Colon and Rectum 53: 213-218, 2010.
5. Reid, R. I. and K. Luo, ``Site-Specific Prolapse Surgery. II. 
Vaginal Paravaginal Repair Augmented With Either Synthetic Mesh or 
Remodeling Xenograft.'' International Urogynecology Journal 22(5): 
601-609, 2011.
6. Mouritsen, L., M. Kronschnabl, and G. Lose, ``Long-Term Results 
of Vaginal Repairs With and Without Xenograft Reinforcement.'' 
International Urogynecology Journal 21:467-473, 2010.
7. Armitage, S., E. I. Seman, and M. J. Keirse, ``Use of Surgisis 
for Treatment of Anterior and Posterior Vaginal Prolapse.'' 
Obstetrics and Gynecology International 376251, January 15, 2012.
8. Jeffery, S. T., S. K. Doumouchtsis, S. Parappallil, et al., 
``Outcomes, Recurrence Rates, and Postoperative Sexual Function 
After Secondary Vaginal Prolapse Surgery Using the Small Intestinal 
Submucosal Graft.'' Female Pelvic Medicine & Reconstructive Surgery 
15: 151-156, 2009.
9. Madhu, C., J. Cooke, P. Harber, and D. Holmes, ``Functional 
Outcomes of Posterior Vaginal Wall Repair and Prespinous Colpopexy 
With Biological Small Intestinal Submucosal (SIS) Graft.'' Archives 
of Gynecology and Obstetrics May 8, 2014.
10. Feldner, P. C., R. A. Castro, L. A. Cipolotti, et al., 
``Anterior Vaginal Wall Prolapse: A Randomized Controlled Trial of 
SIS Graft Versus Traditional Colporrhaphy.'' International 
Urogynecology Journal 21: 1057-1063, 2010.
11. Robert, M., I. Girard, E. Brennand, et al., ``Absorbable Mesh 
Augmentation Compared With No Mesh for Anterior Prolapse: A 
Randomized Controlled Trial.'' Obstetrics & Gynecology 123: 288-294, 
2014.
12. Sung, V., C. Rardin, C. Raker, et al., ``Porcine Subintestinal 
Submucosal Graft Augmentation for Rectocele Repair.'' Obstetrics & 
Gynecology 119: 125-133, 2012.
13. Pelvic Floor Disorders Registry. Frequently Asked Questions. 
Available at http://www.pfdr.org/p/cm/ld/fid=440.
14. Geoffrion, R., M. Murphy, and M. Robert, ``Vaginal Paravaginal 
Repair With Porcine Small Intestine Submucosa: Midterm Outcomes.'' 
Female Pelvic Medicine & Reconstructive Surgery 17(4): 174-179, 
2011.
15. Abed, H., D. D. Rahn, L. Lowenstein, et al., ``Incidence and 
Management of Graft Erosion, Wound Granulation, and Dyspareunia 
Following Vaginal Prolapse Repair With Graft Materials: A Systematic 
Review.'' International Urogynecology Journal 22:789-798, 2011.
16. ``Update on Serious Complications Associated With Transvaginal 
Placement of Surgical Mesh for Pelvic Organ Prolapse: FDA Safety 
Communication,'' issued on July 13, 2011. Available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm262435.htm.
17. Onwude, J. L., ``Genital Prolapse in Women.'' BMJ Clinical 
Evidence (Online) March 14, 2012.
18. Maher, C., ``Anterior Vaginal Compartment Surgery.'' 
International Urogynecology Journal 24: 1791-1802, 2013.
19. Maher, C., B. Feiner, K. Baessler, and C. Schmid, ``Surgical 
Management of Pelvic Organ Prolapse in Women.'' Cochrane Database of 
Systematic Reviews 4:CD004014, April 30, 2013.
20. Barski, D., T. Otto, and H. Gerullis, ``Systematic Review and 
Classification of Complications After Anterior, Posterior, Apical, 
and Total Vaginal Mesh Implantation for Prolapse Repair.'' Surgical 
Technology International 24:217-224, March 2014.
21. Su, T. H., H. H. Lau, W. C. Huang, et al., ``Single-Incision 
Mesh Repair Versus Traditional Native Tissue Repair for Pelvic Organ 
Prolapse: Results of a Cohort Study.'' International Urogynecology 
Journal January 28, 2014.
22. Azais, H., C. J. Charles, P. Delporte, and P. Debondinance, 
``Prolapse Repair Using the Elevate Kit: Prospective Study on 70 
Patients.'' International Urogynecology Journal March 1, 2012.
23. Stanford, E. J., R. D. Moore, J. P. Roovers, et al., ``Elevate 
Anterior/Apical: 12-month Data Showing Safety and Efficacy in 
Surgical Treatment of Pelvic Organ Prolapse.'' Female Pelvic 
Medicine & Reconstructive Surgery 19(2): 79-83, March-April, 2013.
24. Lubkan J., J. P. Roovers, D. M. Vandrie, et al., ``Single-
Incision Apical and Posterior Mesh Repair: 1-year Prospective 
Outcomes.'' International Urogynecology Journal March 15, 2012.
25. Rapp, D. E., A. B. King, B. Rowe, and J. P. Wolters, 
``Comprehensive Evaluation of Anterior Elevate System in the 
Treatment of Anterior and Apical Pelvic Floor Descent: 2-year 
Follow-up.'' Journal of Urology 191(2): 389-394, February 2014.
26. Wong, V., K. L. Shek, A. Rane, et al., ``A Comparison of Two 
Different Mesh Kit Systems for Anterior Compartment Prolapse 
Repair.'' Australian and New Zealand Journal of Obstetrics and 
Gynaecology February 25, 2014.
27. Moore, R. D., G. K. Mitchell, and J. R. Miklos, ``Single-
Incision Vaginal Approach To Treat Cystocele and Vault Prolapse With 
an Anterior Wall Mesh Anchored Apically to the Sacrospinous 
Ligaments.'' International Urogynecology Journal 23(1): 85-91, 2012.
28. Gustapane, S., M. Leombroni, E. Falo, et al., ``Surgical Repair 
of Pelvic Organ Prolapse and Follow-Up: An Institutional Multi-
Center Experience.'' World Journal of Obstetrics and Gynecology 
2(4): 176-180, 2013.
29. Sirls, L. T., G. P. McLennan, K. A. Killinger, et al., 
``Exploring Predictors of Mesh Eexposure After Vaginal Prolapse 
Repair.'' Female Pelvic Medicine & Reconstructive Surgery 19(4): 
206-209, 2013.
30. Sinhal, D., J. Iyer, M. Mous, et al., ``Anterior-Apical Mesh 
Repair System in

[[Page 361]]

an Ambulatory Setting.'' Ambulatory Surgery 19(4): 130-133, 2013.
31. Brennand, E. A., D. Bhayana, S. Tang, et al., ``Anchor Placement 
and Subsequent Movement in a Mesh Kit With Self-Fixating Tips: 6-
Month Follow-Up of a Prospective Cohort.'' British Journal of 
Obstetrics and Gynaecology; DOI:10.1111/1471-0528.12536, 2014.

List of Subjects in 21 CFR Part 884

    Medical devices.

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

PART 884--OBSTETRICAL AND GYNECOLOGICAL DEVICES

0
1. The authority citation for 21 CFR part 884 continues to read as 
follows:

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


0
2. Add Sec.  884.5980 to subpart F to read as follows:


Sec.  884.5980  Surgical mesh for transvaginal pelvic organ prolapse 
repair.

    (a) Identification. Surgical mesh for transvaginal pelvic organ 
prolapse repair is a prescription device intended to reinforce soft 
tissue in the pelvic floor. This device is a porous implant that is 
made of synthetic material, non-synthetic material, or a combination of 
synthetic and non-synthetic materials. This device does not include 
surgical mesh for other intended uses (Sec.  878.3300 of this chapter).
    (b) Classification. Class III (premarket approval).

    Dated: December 30, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-33165 Filed 1-4-16; 8:45 am]
 BILLING CODE 4164-01-P