81_FR_355 81 FR 353 - Obstetrical and Gynecological Devices; Reclassification of Surgical Mesh for Transvaginal Pelvic Organ Prolapse Repair

81 FR 353 - Obstetrical and Gynecological Devices; Reclassification of Surgical Mesh for Transvaginal Pelvic Organ Prolapse Repair

DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Federal Register Volume 81, Issue 2 (January 5, 2016)

Page Range353-361
FR Document2015-33165

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.

Federal Register, Volume 81 Issue 2 (Tuesday, January 5, 2016)
[Federal Register Volume 81, Number 2 (Tuesday, January 5, 2016)]
[Rules and Regulations]
[Pages 353-361]
From the Federal Register Online  [www.thefederalregister.org]
[FR Doc No: 2015-33165]



[[Page 353]]

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

[[Page 354]]


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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

[[Page 356]]

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

[[Page 358]]

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



                                                                                                        Vol. 81                           Tuesday,
                                                                                                        No. 2                             January 5, 2016




                                                                                                        Part III


                                                                                                        Department of Health and Human Services
                                                                                                        Food and Drug Administration
                                                                                                        21 CFR Part 884
                                                                                                        Obstetrical and Gynecological Devices; Reclassification of Surgical Mesh
                                                                                                        for Transvaginal Pelvic Organ Prolapse Repair; Final Rule
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                                                  354                 Federal Register / Vol. 81, No. 2 / Tuesday, January 5, 2016 / Rules and Regulations

                                                  DEPARTMENT OF HEALTH AND                                along with a proposed regulation                       defined in section 513(a)(3) of the FD&C
                                                  HUMAN SERVICES                                          classifying the device; and (3) published              Act and 21 CFR 860.7(c)(2). (See, e.g.,
                                                                                                          a final regulation classifying the device.             Gen. Medical Co. v. FDA, 770 F.2d 214
                                                  Food and Drug Administration                            FDA has classified most                                (D.C. Cir. 1985); Contact Lens Mfrs.
                                                                                                          preamendments devices under these                      Assoc. v. FDA, 766 F.2d 592 (D.C. Cir.
                                                  21 CFR Part 884                                         procedures.                                            1985), cert. denied, 474 U.S. 1062
                                                                                                             Devices that were not in commercial                 (1986).)
                                                  [Docket No. FDA–2014–N–0297]
                                                                                                          distribution prior to May 28, 1976                        To be considered in the
                                                  Obstetrical and Gynecological                           (generally referred to as                              reclassification process, the ‘‘valid
                                                  Devices; Reclassification of Surgical                   postamendments devices), are                           scientific evidence’’ upon which the
                                                  Mesh for Transvaginal Pelvic Organ                      automatically classified by section                    Agency relies must be publicly
                                                  Prolapse Repair                                         513(f) of the FD&C Act into class III                  available. Publicly available information
                                                                                                          without any FDA rulemaking process.                    excludes trade secret and/or
                                                  AGENCY:    Food and Drug Administration,                Those devices remain in class III and                  confidential commercial information,
                                                  HHS.                                                    require premarket approval unless, and                 e.g., the contents of a pending premarket
                                                  ACTION:   Final order.                                  until, the device is reclassified into class           approval application (PMA). (See
                                                                                                          I or II or FDA issues an order finding the             section 520(c) of the FD&C Act (21
                                                  SUMMARY:    The Food and Drug                           device to be substantially equivalent, in              U.S.C. 360j(c)).)
                                                  Administration (FDA or the Agency) is                   accordance with section 513(i) of the                     Section 513(e)(1) of the FD&C Act sets
                                                  issuing a final order to reclassify                     FD&C Act, to a predicate device that                   forth the process for issuing a final
                                                  surgical mesh for transvaginal pelvic                   does not require premarket approval.                   reclassification order. Specifically, prior
                                                  organ prolapse (POP) repair from class                  The Agency determines whether new                      to the issuance of a final order
                                                  II to class III. FDA is reclassifying these             devices are substantially equivalent to                reclassifying a device, the following
                                                  devices based on the determination that                 predicate devices by means of                          must occur: (1) Publication of a
                                                  general controls and special controls                   premarket notification procedures in                   proposed order in the Federal Register;
                                                  together are not sufficient to provide                  section 510(k) of the FD&C Act (21                     (2) a meeting of a device classification
                                                  reasonable assurance of safety and                      U.S.C. 360(k)) and 21 CFR part 807.                    panel described in section 513(b) of the
                                                  effectiveness for this device, and these                   On July 9, 2012, the Food and Drug                  FD&C Act; and (3) consideration of
                                                  devices present a potential unreasonable                Administration Safety and Innovation                   comments to a public docket.
                                                  risk of illness or injury. The Agency is                Act (FDASIA) (Pub. L. 112–144) was                        FDA published a proposed order (the
                                                  reclassifying surgical mesh for                         enacted. Section 608(a) of FDASIA                      513(e) proposed order) to reclassify this
                                                  transvaginal POP repair on its own                      amended section 513(e) of the FD&C                     device in the Federal Register of May 1,
                                                  initiative based on new information.                    Act, changing the mechanism for                        2014 (79 FR 24634). FDA received and
                                                  DATES: This order is effective on January
                                                                                                          reclassifying a device from rulemaking                 has considered approximately 200
                                                                                                          to an administrative order. Section                    comments on this 513(e) proposed
                                                  5, 2016.
                                                                                                          513(e) of the FD&C Act provides that                   order, as discussed in section II.
                                                  FOR FURTHER INFORMATION CONTACT:                                                                                  FDA held a meeting on September 8
                                                                                                          FDA may, by administrative order,
                                                  Sharon Andrews, Center for Devices and                  reclassify a device based upon ‘‘new                   and 9, 2011 (76 FR 41507, July 14, 2011)
                                                  Radiological Health, 10903 New                          information.’’ FDA can initiate a                      of the Obstetrics and Gynecology
                                                  Hampshire Ave., Bldg. 66, Rm. G110,                     reclassification under section 513(e) of               Devices Panel of the Medical Devices
                                                  Silver Spring, MD 20993, 301–796–                       the FD&C Act or an interested person                   Advisory Committee (‘‘the Panel’’), a
                                                  6529, Sharon.Andrews@fda.hhs.gov.                       may petition FDA to reclassify a device.               device classification panel described in
                                                  SUPPLEMENTARY INFORMATION:                              The term ‘‘new information,’’ as used in               section 513(b) of the FD&C Act, to
                                                                                                          section 513(e) of the FD&C Act, includes               discuss whether surgical mesh for
                                                  I. Background—Regulatory Authorities
                                                                                                          information developed as a result of a                 transvaginal POP repair should be
                                                     The Federal Food, Drug, and Cosmetic                 reevaluation of the data before the                    reclassified into class III or remain in
                                                  Act (the FD&C Act), as amended,                         Agency when the device was originally                  class II (Ref. 1). The Panel discussed a
                                                  established a comprehensive system for                  classified, as well as information not                 number of serious adverse events
                                                  the regulation of medical devices                       presented, not available, or not                       associated with use of surgical mesh for
                                                  intended for human use. Section 513 of                  developed at that time. (See, e.g.,                    transvaginal POP repair. The Panel
                                                  the FD&C Act (21 U.S.C. 360c)                           Holland-Rantos Co. v. United States                    consensus was that the safety of surgical
                                                  established three categories (classes) of               Department of Health, Education, and                   mesh for transvaginal POP repair is not
                                                  devices, reflecting the regulatory                      Welfare, 587 F.2d 1173, 1174 n.1 (D.C.                 well established and that, depending on
                                                  controls needed to provide reasonable                   Cir. 1978); Upjohn v. Finch, 422 F.2d                  the compartment, placement of surgical
                                                  assurance of their safety and                           944 (6th Cir. 1970); Bell v. Goddard, 366              mesh for transvaginal POP repair may
                                                  effectiveness. The three categories of                  F.2d 177 (7th Cir. 1966).)                             not be more effective than traditional
                                                  devices are class I (general controls),                    Reevaluation of the data previously                 ‘‘native-tissue’’ repair without mesh. As
                                                  class II (special controls), and class III              before the Agency is an appropriate                    such, the Panel concluded that the risk-
                                                  (premarket approval).                                   basis for subsequent action where the                  benefit profile of surgical mesh for
                                                     Under section 513(d) of the FD&C Act,                reevaluation is made in light of newly                 transvaginal POP repair is not well
                                                  devices that were in commercial                         available authority (see Bell, 366 F.2d at             established. The Panel consensus was
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                                                  distribution before the enactment of the                181; Ethicon, Inc. v. FDA, 762 F.Supp.                 that general controls and special
                                                  1976 amendments, May 28, 1976                           382, 388–391 (D.D.C. 1991)), or in light               controls together would not be sufficient
                                                  (generally referred to as preamendments                 of changes in ‘‘medical science’’                      to provide reasonable assurance of the
                                                  devices), are classified after FDA has: (1)             (Upjohn, 422 F.2d at 951). Whether data                safety and effectiveness of surgical mesh
                                                  Received a recommendation from a                        before the Agency are old or new data,                 for transvaginal POP repair, and that
                                                  device classification panel (an FDA                     the ‘‘new information’’ to support                     these devices should be reclassified
                                                  advisory committee); (2) published the                  reclassification under section 513(e)                  from class II to class III (Ref. 1). FDA is
                                                  panel’s recommendation for comment,                     must be ‘‘valid scientific evidence,’’ as              not aware of new information since the


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                                                                      Federal Register / Vol. 81, No. 2 / Tuesday, January 5, 2016 / Rules and Regulations                                              355

                                                  Panel meeting that would provide a                      commenters are consistent with those                   that the safety and effectiveness of
                                                  basis for a different recommendation or                 addressed in the 513(e) proposed order                 surgical mesh for transvaginal POP
                                                  findings.                                               preamble and discussed at the 2011                     repair has not been established and that
                                                     In the 513(e) proposed order, FDA                    Panel meeting. The comments did not                    the collection of additional clinical
                                                  also proposed to reclassify surgical                    identify any adverse event information                 evidence on these devices is needed.
                                                  instrumentation for urogynecologic                      that was not already considered by FDA                 Such additional evidence may provide
                                                  surgical mesh procedures from class I to                and the Panel.                                         information to allow FDA to impose
                                                  class II and establish special controls.                   (Comment 2) Approximately 50                        controls to mitigate the risks and more
                                                  FDA is not finalizing the proposed                      comments requested reclassification of                 clearly characterize the benefits of these
                                                  reclassification and special controls for               surgical mesh for indications other than               devices. In addition, FDA believes there
                                                  surgical instrumentation for use with                   transvaginal POP repair, including for                 are potential benefits from surgical
                                                  urogynecologic surgical mesh at this                    SUI and hernia.                                        mesh used for transvaginal POP repair
                                                  time. As stated in the 513(e) proposed                     (Response) Surgical mesh for                        including treatment of POP in
                                                  order preamble, FDA will convene a                      indications other than transvaginal POP                appropriately selected women with
                                                  panel to discuss specialized surgical                   repair is outside the scope of the 513(e)              severe or recurrent prolapse. As such,
                                                  instrumentation for use with                            proposed order and this document. In                   FDA has not determined that this device
                                                  urogynecologic surgical mesh prior to                   the 513(e) proposed order (79 FR 24634                 presents an unreasonable and
                                                  finalizing reclassification of                          at 24636), FDA stated that this proposed               substantial risk of illness or injury.
                                                  instrumentation for this use. On                        order does not include surgical mesh                      FDA also does not believe there is
                                                  February 26, 2016, the Gastroenterology                 indicated for surgical treatment of stress             sufficient evidence at this time to
                                                  and Urology Devices Panel of the                        urinary incontinence, sacrocolpopexy                   support a mandatory recall of this
                                                  Medical Devices Advisory Committee                      (transabdominal POP repair), hernia                    device. Under section 518(e) of the
                                                  will have a panel meeting to discuss and                repair, and other non-urogynecologic                   FD&C Act (21 U.S.C. 360h(e)), if the
                                                  make recommendations for                                indications.                                           Secretary finds that there is a reasonable
                                                  reclassification of these specialized                      (Comment 3) Approximately 50                        probability that a device intended for
                                                  surgical instrumentation devices.                       comments requested a ban, recall, or                   human use would cause serious,
                                                                                                          ‘‘suspension of use’’ of all surgical mesh             adverse health consequences or death,
                                                  II. Public Comments in Response to the                  devices.                                               the Secretary shall issue an order
                                                  513(e) Proposed Order                                      (Response) As stated previously,                    requiring the appropriate person
                                                     In response to the 513(e) proposed                   surgical mesh for indications other than               (including the manufacturers, importers,
                                                  order to reclassify surgical mesh for                   transvaginal POP repair is outside the                 distributors, or retailers of the device) to
                                                  transvaginal POP repair, FDA received                   scope of this final order. For the reasons             immediately cease distribution of such
                                                  approximately 200 comments. The                         discussed in this document, FDA does                   device, and to immediately notify health
                                                  comments and FDA’s responses to the                     not believe that a ban, recall or                      professionals and device user facilities
                                                  comments are summarized in this                         suspension of use of surgical mesh for                 of the order and to instruct such
                                                  section. Certain comments are grouped                   transvaginal POP repair is warranted at                professionals and facilities to cease use
                                                  together under a single number because                  this time.                                             of such device.
                                                  the subject matter of the comments is                      Section 516 of the FD&C Act (21                        FDA does not believe a mandatory
                                                  similar. The number assigned to each                    U.S.C. 360f) authorizes FDA to ban a                   recall of all currently marketed surgical
                                                  comment is purely for organizational                    device when, on the basis of all                       mesh for transvaginal POP repair is
                                                  purposes and does not signify the                       available data and information, FDA                    warranted. Based on a review of the
                                                  comment’s value or importance or the                    finds that the device presents                         published literature as described in the
                                                  order in which it was submitted.                        substantial deception or an                            513(e) proposed order preamble and this
                                                     (Comment 1) Approximately 70                         unreasonable and substantial risk of                   document, input from clinical
                                                  comments were received from                             illness or injury and, where such                      organizations, and the Panel’s
                                                  individuals or family members of                        deception or risk could be corrected or                recommendations, FDA believes that
                                                  individuals who underwent mesh repair                   eliminated by labeling or change in                    there is not sufficient evidence at this
                                                  for POP, stress urinary incontinence                    labeling and with respect to which the                 time to support a finding that there is a
                                                  (SUI), and/or hernias and reported                      Secretary of the Department of Health                  reasonable probability that surgical
                                                  complications or adverse events                         and Human Services (Secretary)                         mesh for transvaginal repair of POP
                                                  experienced during or after their                       provided written notice to the                         would cause serious adverse health
                                                  procedures. The complications and                       manufacturer specifying the deception                  consequences or death. As described in
                                                  adverse events reported included organ                  or risk of illness or injury, the labeling             the 513(e) proposed order preamble and
                                                  perforation, bleeding, chronic pain,                    or change in labeling to correct the                   discussed at the 2011 Panel meeting, the
                                                  mesh exposure or extrusion into the                     deception or eliminate or reduce such                  safety and effectiveness of surgical mesh
                                                  vagina and/or visceral organs (in some                  risk, and the period within which such                 for transvaginal repair of POP has not
                                                  cases requiring additional surgery),                    labeling or change in labeling was to be               been established and these devices
                                                  infection, atypical vaginal discharge,                  done, such labeling or change in                       should be evaluated in clinical studies
                                                  painful sexual intercourse, self-                       labeling was not done within such                      that compare the device to native tissue
                                                  catheterization, recurrent prolapse and/                period.                                                repair in order to establish a reasonable
                                                  or incontinence, additional corrective                     FDA does not believe there is                       assurance of safety and effectiveness.
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                                                  surgery, and other permanent and/or                     sufficient evidence at this time to                       It is unclear what commenters were
                                                  life-altering adverse events.                           support the banning of this device.                    referencing when they asked FDA to
                                                     (Response) FDA appreciates the                       Based on a review of the published                     ‘‘suspend the use’’ of these devices. As
                                                  comments received from individuals                      literature, as described in the 513(e)                 stated previously, FDA does not believe
                                                  sharing their experiences following                     proposed order preamble and this                       a ban or recall is warranted at this time,
                                                  surgical mesh repair for POP, SUI, and/                 document, input from clinical                          and as stated in this document, there are
                                                  or hernias. The complications and                       organizations, and the Panel’s                         other actions FDA has taken and may
                                                  adverse events reported by these                        recommendations, FDA has determined                    take in the future to ensure that there is


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

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


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                                                                      Federal Register / Vol. 81, No. 2 / Tuesday, January 5, 2016 / Rules and Regulations                                             357

                                                  Stage 1 as the cutoff for anatomic                      retrospective chart review (N = 59) (Ref.              reclassifying all of these devices from
                                                  success.                                                14). This report does define anatomic                  class II to class III. FDA’s decision is in
                                                     One publication described a                          success at the hymenal ring. Objective                 line with the 2011 Panel, which did not
                                                  retrospective case review without native                recurrence of prolapse in this study was               recommend stratification of surgical
                                                  tissue control (Ref. 7). This review (N =               approximately 31 percent.                              mesh for transvaginal POP repair by
                                                  65) found a subjective success (no                         Regarding mesh exposure/erosion, the                material characteristics.
                                                  symptoms and no bulge beyond the                        publications cited by the commenter                       (Comment 6) Approximately 20
                                                  hymen) rate of 92 percent. Reoperation                  suggests that the risk of vaginal                      comments stated that patients were not
                                                  rate for de novo and recurrent prolapse                 exposure/erosion for the non-                          adequately informed of the possible
                                                  was 7.7 percent, and three women had                    crosslinked mesh is low. In the 513(e)                 complications following mesh
                                                  repeat surgery at the same anatomic site                proposed order preamble, FDA noted                     implantation or that patients were not
                                                  (anterior compartment). Because this                    that the incidence of mesh exposure did                informed prior to surgery that mesh
                                                  study did not include a control group,                  not differ between nonabsorbable                       would be implanted.
                                                  we are unable to compare safety and                     synthetic mesh (10.3 percent) and                         (Response) FDA believes that patients
                                                  effectiveness outcomes between patients                 biologic graft material (10.1 percent)                 should be adequately informed
                                                  who received mesh and patients who                      (Ref. 15).                                             regarding the possible complications
                                                  underwent native tissue repair.                            For other types of surgical                         associated with surgical mesh. As stated
                                                     Two publications described                           complications, one RCT (N = 56) found                  in the FDA Safety Communication
                                                  prospective cohorts. In one small series                that the number of complications in the                published in July 2011 (Ref. 16), health
                                                  (N = 21), women with recurrent                          mesh group was greater compared to the                 care providers should: (1) Inform
                                                  prolapse underwent anterior, posterior,                 native tissue repair group (Ref. 10).                  patients that implantation of surgical
                                                  or combined anterior/posterior repair                   Blood loss was greater for mesh versus                 mesh is permanent and that some
                                                  with non-crosslinked biologic mesh                      native tissue rectocele repair in another              complications associated with the
                                                  (Ref. 8). Mean POP–Q scores                             RCT (N = 160) (Ref. 12). In the same                   implanted mesh may require additional
                                                  preoperatively were Ba = 0.63 versus Ba                 RCT, there was a trend towards                         surgery that may or may not correct the
                                                  = 1.75 postoperatively. Preoperative Bp                 increased risk of wound separation                     complication; (2) inform patients about
                                                  score was ¥0.2 versus Bp ¥2.2                           following non-crosslinked graft repair                 the potential for serious complications
                                                  postoperatively. The authors reported a                 versus native tissue repair; however, the              and their effect on quality of life,
                                                  mean followup of 29 months. Six                         outcome did not reach statistical                      including pain during sexual
                                                  patients reported persistent bulge, and                 significance.                                          intercourse, scarring, and narrowing of
                                                  eight patients reported vaginal                            In addition, serious adverse events are             the vaginal wall in POP repair using
                                                  discomfort. This study has a small                      reported in association with non-                      surgical mesh; and (3) provide patients
                                                  sample size and does not allow for                      crosslinked biologic graft, including                  with a copy of the patient labeling from
                                                  comparison to native tissue repair.                     pain necessitating resurgery (Ref. 14). In             the surgical mesh manufacturer, if
                                                     The other prospective cohort study (N                this study, surgical complications                     available. The 2011 Safety
                                                  = 50) evaluated patient-reported                        included cystotomy (6.8 percent) and                   Communication also includes
                                                  outcomes at 6 months following                          enterotomy (1.7 percent). Twenty-four                  recommendations for patients to help
                                                  posterior compartment repair                            percent of subjects had postoperative                  them obtain the appropriate information
                                                  augmented with non-crosslinked mesh                     voiding dysfunction, and there was a 5.1               prior to a surgical mesh repair.
                                                  (Ref. 9). Although significant                          percent rate of hemorrhage requiring                      The Panel recommended that FDA
                                                  improvements were noted for vaginal                     transfusion. (It is unclear whether these              focus on development of patient
                                                  symptoms, sexual matters score and                      complications were device-related). The                labeling and provide patients with
                                                  quality of life on the International                    rate of dyspareunia at followup was 8.3                benefit-risk information on available
                                                  Consultation on Incontinence                            percent. The study did not include a                   treatment options for POP, including
                                                  Questionnaire vaginal symptoms                          control group, so it is unknown how the                surgical and nonsurgical options, to
                                                  questionnaire, anatomic outcomes were                   benefits and risks of graft-augmented                  help patients understand long-term
                                                  not collected. Therefore, effectiveness                 repair with the non-crosslinked biologic               safety and effectiveness outcomes (Ref.
                                                  outcomes cannot be evaluated from this                  graft would have compared with a                       1, p. 150).
                                                  study.                                                  native tissue repair.                                     For these reasons, in the findings of
                                                     Only three of the remaining                             In summary, there is insufficient                   the 515(b) proposed order, which are
                                                  publications described prospective                      available evidence from prospective                    adopted as amended in the 515(b) final
                                                  randomized controlled trials (RCTs)                     studies using an appropriate primary                   order that is being published elsewhere
                                                  comparing anterior or posterior vaginal                 endpoint for anatomic success on which                 in this issue of the Federal Register,
                                                  repair using non-crosslinked biologic                   to evaluate the effectiveness of                       FDA asserted that manufacturers should
                                                  graft versus native tissue repair (Refs. 10             transvaginal POP repair using non-                     include in their PMAs for these devices
                                                  through 12). None of the three RCTs                     crosslinked biologic mesh versus native                professional and patient labeling, and
                                                  defined anatomic success as the leading                 tissue repair. The available clinical                  that the patient labeling would be
                                                  edge of prolapse at or above the                        outcomes provide evidence that non-                    expected to include, among other
                                                  hymenal ring, which is considered a                     crosslinked biologic mesh is associated                things, the risks and benefits of the
                                                  more clinically relevant outcome                        with adverse events. There are no data                 device and available treatment options.
                                                  compared to POP–Q score. The criterion                  from RCTs with long-term followup that                 Therefore, it is expected that PMAs for
asabaliauskas on DSK5VPTVN1PROD with RULES




                                                  for anatomic success of prolapse repair                 demonstrate clinical effectiveness of                  these devices include professional and
                                                  in the American Urogynecologic Society                  this material for transvaginal POP repair              patient labeling, and that the patient
                                                  (AUGS) Pelvic Floor Disorders Registry                  compared to native tissue repair.                      labeling include, among other things,
                                                  is leading edge at or above the hymen                      As a result of these findings, FDA is               the risks and benefits of the device and
                                                  (Ref. 13).                                              not differentiating between non-                       available treatment options.
                                                     The final publication identified by the              crosslinked biologic grafts and synthetic                 (Comment 7) Approximately 30
                                                  commenter described prospective                         mesh for transvaginal POP repair in this               comments stated that surgical mesh
                                                  followup of a cohort assembled from a                   reclassification order and is                          should be adequately tested, including


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

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


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                                                                      Federal Register / Vol. 81, No. 2 / Tuesday, January 5, 2016 / Rules and Regulations                                            359

                                                  respectively (p = 0.006) (79 FR 24637).’’               success among mesh subjects would                      all transvaginal mesh for POP repair
                                                  The 22 percent cited by FDA in the                      have exceeded that of native tissue                    regardless of location of repair.
                                                  513(e) proposed order preamble was not                  repair.                                                   (Comment 11) One comment stated
                                                  specific for anterior repair, but rather                   One publication that evaluated more                 that the 513(e) proposed order makes
                                                  included all vaginal compartments.                      clinical and/or subjective outcomes                    definitive statements regarding benefit/
                                                    In addition to the four recent                        compared two mesh products (Ref. 26).                  risk, when in fact additional studies are
                                                  systematic reviews discussed                            The failure of the mesh repair ranged                  needed to establish benefit/risk.
                                                  previously, the commenter cited 43                      from 24 percent to 46 percent,                            (Response) FDA disagrees that the
                                                  published reports, of which 31 are                      depending on the outcome measure.                      513(e) proposed order makes definitive
                                                  abstracts or poster presentations. Based                Mesh exposure occurred at a rate of 8                  statements regarding benefit/risk.
                                                  on the limited scientific evidence in                   percent. Pelvic pain was reported at 7.4               Throughout the 513(e) proposed order
                                                  these abstracts and poster presentations,               percent, and of study subjects who were                preamble, FDA described its
                                                  they are difficult to evaluate, and                     sexually active, 12.7 percent reported                 conclusions as ‘‘tentative.’’
                                                  therefore, FDA was unable to draw any                   painful intercourse. In one prospective                III. The Final Order
                                                  conclusions from these publications.                    study (N = 30), no anatomic outcomes
                                                  The comment stated that collectively,                   were reported; however, the report                        Under section 513(e) of the FD&C Act,
                                                  the studies report mesh exposure rates                  stated that no patients had symptoms of                FDA is adopting its findings as
                                                  of 0 to 8 percent and of the mesh                       recurrent prolapse at 12 months of                     published in the preamble to the 513(e)
                                                  exposures, only approximately 38                        followup. Two patients in this cohort                  proposed order (79 FR 24634). FDA is
                                                  percent required surgical intervention.                 had mesh erosion which required                        issuing this final order to reclassify
                                                  The comment stated this outcome                         partial mesh excision (Ref. 28).                       surgical mesh for transvaginal POP
                                                  represents a reduction compared to the                     The remaining publications cited in                 repair from class II to class III. FDA is
                                                  7.2 percent rate cited in the 513(e)                    the comment address mesh exposure,                     reclassifying these devices based on the
                                                  proposed order. However, the 7.2                        mesh repair as an ambulatory                           determination that general controls and
                                                  percent rate cited by FDA in the 513(e)                 procedure, and stability of an anchor                  special controls together are not
                                                  proposed order preamble was the rate of                 device used to attach the mesh to an                   sufficient to provide reasonable
                                                  reoperation due to any complication,                    anatomic target (Refs. 29 through 31).                 assurance of safety and effectiveness for
                                                  and not specifically for mesh exposure-                 The rate of mesh exposure in the first                 this device. In addition, in the absence
                                                  related complications.                                  study was 8.1 percent (Ref. 28). None of               of an established positive benefit-risk
                                                    The comment also stated that the                                                                             profile, FDA has determined that the
                                                                                                          these publications compared mesh
                                                  more recent literature defines success as                                                                      risks to health associated with the use
                                                                                                          repair to native tissue repair, nor does
                                                  improved anatomic and subjective                                                                               of surgical mesh for transvaginal POP
                                                                                                          any reflect a study designed to evaluate
                                                  outcomes compared to native tissue                                                                             repair identified previously present a
                                                                                                          surgical success.
                                                  repair. Of the publications that were not                                                                      potential unreasonable risk of illness or
                                                  abstracts or posters, there is only one in                 In summary, FDA concludes that the
                                                                                                                                                                 injury.
                                                  which surgical mesh repair was                          literature published since the 513(e) and                 FDA has modified the proposed
                                                  compared to native tissue (Ref. 21). In                 515(b) proposed orders were issued and                 identification in § 884.5980(a) for
                                                  that study, the primary outcome was                     the additional literature cited by the                 surgical mesh for transvaginal pelvic
                                                  ideal anatomic support based on POP–                    commenter further supports the                         organ prolapse repair to clarify that the
                                                  Q stage, and not subjective outcomes.                   reclassification of surgical mesh for                  materials of construction may include
                                                  Anatomic success, defined as POP–Q                      transvaginal POP repair from class II to               synthetic material, non-synthetic
                                                  stage 0 or 1 was greater for the surgical               class III.                                             material, or a combination of synthetic
                                                  mesh repair in the anterior                                (Comment 10) One comment noted                      and non-synthetic materials.
                                                  compartment; however, improvement in                    that direct comparison of safety results
                                                  quality of life was not statistically                   between sacrocolpopexy, transvaginal                   IV. Analysis of Environmental Impact
                                                  significant between groups. In addition,                repair, and native tissue repair can be                   The Agency has determined under 21
                                                  subjects in the surgical mesh group had                 misleading if the vaginal repair does not              CFR 25.34(b) that this action is of a type
                                                  statistically significant longer hospital               have a vaginal vault component.                        that does not individually or
                                                  stays, operative time, and estimated                       (Response) Based on the evidence                    cumulatively have a significant effect on
                                                  blood loss.                                             cited in the 513(e) proposed order                     the human environment. Therefore,
                                                    With one exception, of the                            preamble, FDA concluded that the types                 neither an environmental assessment
                                                  publications cited by the commenter to                  of risks associated with transvaginal                  nor an environmental impact statement
                                                  represent success rates for one line of                 mesh for POP repair are similar across                 is required.
                                                  mesh products, the definition of a                      different vaginal compartments. FDA is
                                                  success was ideal anatomic support                      unaware of any new evidence that                       V. Paperwork Reduction Act of 1995
                                                  (Refs. 22 through 27). As noted in the                  supports the conclusion that the types                   This final order refers to previously
                                                  513(e) proposed order preamble, ideal                   of risk associated with transvaginal                   approved collections of information
                                                  anatomic support is not a prerequisite                  mesh for POP are different across                      found in FDA regulations. These
                                                  for improvement in patient symptoms.                    different vaginal compartments.                        collections of information are subject to
                                                  As stated previously in this document,                  However, FDA acknowledges that the                     review by the Office of Management and
                                                  the anatomic criterion for success                      frequency of different types of adverse                Budget (OMB) under the Paperwork
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                                                  following surgical repair of prolapse in                events may vary across different vaginal               Reduction Act of 1995 (44 U.S.C. 3501–
                                                  the AUGS Pelvic Floor Disorders                         compartments. FDA’s conclusion is in                   3520). The collections of information in
                                                  Registry is absence of leading edge of                  line with the Panel, which did not                     21 CFR part 814, subpart B, have been
                                                  prolapse beyond the hymen, not POP–                     recommend that reclassification be                     approved under OMB control number
                                                  Q Stage ≤ 1. In addition, because these                 stratified by compartment. For the                     0910–0231; and the collections of
                                                  studies did not compare outcomes                        reasons discussed in the 513(e)                        information under 21 CFR part 801 have
                                                  between mesh repair and native tissue                   proposed order preamble and in this                    been approved under OMB control
                                                  repair, it is unknown whether the                       document, the reclassification applies to              number 0910–0485.


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

                                                  VI. Codification of Orders                                   of a Bioprosthetic Graft.’’ Diseases of the       17. Onwude, J. L., ‘‘Genital Prolapse in
                                                                                                               Colon and Rectum 53: 213–218, 2010.                    Women.’’ BMJ Clinical Evidence (Online)
                                                     Prior to the amendments by FDASIA,                   5. Reid, R. I. and K. Luo, ‘‘Site-Specific                  March 14, 2012.
                                                  section 513(e) of the FD&C Act provided                      Prolapse Surgery. II. Vaginal Paravaginal         18. Maher, C., ‘‘Anterior Vaginal
                                                  for FDA to issue regulations to reclassify                   Repair Augmented With Either Synthetic                 Compartment Surgery.’’ International
                                                  devices. Although section 513(e) of the                      Mesh or Remodeling Xenograft.’’                        Urogynecology Journal 24: 1791–1802,
                                                  FD&C Act, as amended, requires FDA to                        International Urogynecology Journal                    2013.
                                                  issue final orders rather than                               22(5): 601–609, 2011.                             19. Maher, C., B. Feiner, K. Baessler, and C.
                                                  regulations, FDASIA also provides for                   6. Mouritsen, L., M. Kronschnabl, and G.                    Schmid, ‘‘Surgical Management of Pelvic
                                                                                                               Lose, ‘‘Long-Term Results of Vaginal                   Organ Prolapse in Women.’’ Cochrane
                                                  FDA to revoke previously issued                              Repairs With and Without Xenograft                     Database of Systematic Reviews
                                                  regulations by order. FDA will continue                      Reinforcement.’’ International                         4:CD004014, April 30, 2013.
                                                  to codify classifications and                                Urogynecology Journal 21:467–473,                 20. Barski, D., T. Otto, and H. Gerullis,
                                                  reclassifications in the Code of Federal                     2010.                                                  ‘‘Systematic Review and Classification of
                                                  Regulations (CFR). Changes resulting                    7. Armitage, S., E. I. Seman, and M. J. Keirse,             Complications After Anterior, Posterior,
                                                  from final orders will appear in the CFR                     ‘‘Use of Surgisis for Treatment of                     Apical, and Total Vaginal Mesh
                                                  as changes to codified classification                        Anterior and Posterior Vaginal                         Implantation for Prolapse Repair.’’
                                                                                                               Prolapse.’’ Obstetrics and Gynecology                  Surgical Technology International
                                                  determinations or as newly codified                          International 376251, January 15, 2012.                24:217–224, March 2014.
                                                  orders. Therefore, under section                        8. Jeffery, S. T., S. K. Doumouchtsis, S.              21. Su, T. H., H. H. Lau, W. C. Huang, et al.,
                                                  513(e)(1)(A)(i) of the FD&C Act, as                          Parappallil, et al., ‘‘Outcomes,                       ‘‘Single-Incision Mesh Repair Versus
                                                  amended by FDASIA, in this final order,                      Recurrence Rates, and Postoperative                    Traditional Native Tissue Repair for
                                                  we are codifying the reclassification of                     Sexual Function After Secondary                        Pelvic Organ Prolapse: Results of a
                                                  surgical mesh for transvaginal POP                           Vaginal Prolapse Surgery Using the                     Cohort Study.’’ International
                                                  repair into class III in 21 CFR 884.5980.                    Small Intestinal Submucosal Graft.’’                   Urogynecology Journal January 28, 2014.
                                                                                                               Female Pelvic Medicine & Reconstructive           22. Azais, H., C. J. Charles, P. Delporte, and
                                                  VII. References                                              Surgery 15: 151–156, 2009.                             P. Debondinance, ‘‘Prolapse Repair
                                                                                                          9. Madhu, C., J. Cooke, P. Harber, and D.                   Using the Elevate Kit: Prospective Study
                                                    The following references are on                            Holmes, ‘‘Functional Outcomes of
                                                  display in the Division of Dockets                                                                                  on 70 Patients.’’ International
                                                                                                               Posterior Vaginal Wall Repair and                      Urogynecology Journal March 1, 2012.
                                                  Management (HFA–305), Food and Drug                          Prespinous Colpopexy With Biological              23. Stanford, E. J., R. D. Moore, J. P. Roovers,
                                                  Administration, 5630 Fishers Lane, Rm.                       Small Intestinal Submucosal (SIS)                      et al., ‘‘Elevate Anterior/Apical: 12-
                                                  1061, Rockville, MD 20852, and are                           Graft.’’ Archives of Gynecology and
                                                                                                                                                                      month Data Showing Safety and Efficacy
                                                  available for viewing by interested                          Obstetrics May 8, 2014.
                                                                                                                                                                      in Surgical Treatment of Pelvic Organ
                                                  persons between 9 a.m. and 4 p.m.,                      10. Feldner, P. C., R. A. Castro, L. A.
                                                                                                                                                                      Prolapse.’’ Female Pelvic Medicine &
                                                                                                               Cipolotti, et al., ‘‘Anterior Vaginal Wall
                                                  Monday through Friday; they are also                                                                                Reconstructive Surgery 19(2): 79–83,
                                                                                                               Prolapse: A Randomized Controlled Trial
                                                  available electronically at http://                          of SIS Graft Versus Traditional
                                                                                                                                                                      March–April, 2013.
                                                  www.regulations.gov. FDA has verified                                                                          24. Lubkan J., J. P. Roovers, D. M. Vandrie,
                                                                                                               Colporrhaphy.’’ International
                                                  the Web site addresses, as of the date                       Urogynecology Journal 21: 1057–1063,                   et al., ‘‘Single-Incision Apical and
                                                  this document publishes in the Federal                       2010.                                                  Posterior Mesh Repair: 1-year
                                                                                                          11. Robert, M., I. Girard, E. Brennand, et al.,             Prospective Outcomes.’’ International
                                                  Register, but Web sites are subject to                                                                              Urogynecology Journal March 15, 2012.
                                                  change over time.                                            ‘‘Absorbable Mesh Augmentation
                                                                                                               Compared With No Mesh for Anterior                25. Rapp, D. E., A. B. King, B. Rowe, and J.
                                                  1. Transcript of the September 8 and 9, 2011,                Prolapse: A Randomized Controlled                      P. Wolters, ‘‘Comprehensive Evaluation
                                                       Meeting of the Obstetrics and                           Trial.’’ Obstetrics & Gynecology 123:                  of Anterior Elevate System in the
                                                       Gynecological Devices Panel. Available                  288–294, 2014.                                         Treatment of Anterior and Apical Pelvic
                                                       at http://www.fda.gov/downloads/                   12. Sung, V., C. Rardin, C. Raker, et al.,                  Floor Descent: 2-year Follow-up.’’
                                                       AdvisoryCommittees/                                     ‘‘Porcine Subintestinal Submucosal Graft               Journal of Urology 191(2): 389–394,
                                                       CommitteesMeetingMaterials/                             Augmentation for Rectocele Repair.’’                   February 2014.
                                                       MedicalDevices/                                         Obstetrics & Gynecology 119: 125–133,             26. Wong, V., K. L. Shek, A. Rane, et al., ‘‘A
                                                       MedicalDevicesAdvisoryCommittee/                        2012.                                                  Comparison of Two Different Mesh Kit
                                                       ObstetricsandGynecologyDevices/                    13. Pelvic Floor Disorders Registry.                        Systems for Anterior Compartment
                                                       UCM275043.pdf and http://                               Frequently Asked Questions. Available                  Prolapse Repair.’’ Australian and New
                                                       www.fda.gov/downloads/                                  at http://www.pfdr.org/p/cm/ld/fid=440.                Zealand Journal of Obstetrics and
                                                       AdvisoryCommittees/                                14. Geoffrion, R., M. Murphy, and M. Robert,                Gynaecology February 25, 2014.
                                                       CommitteesMeetingMaterials/                             ‘‘Vaginal Paravaginal Repair With                 27. Moore, R. D., G. K. Mitchell, and J. R.
                                                       MedicalDevices/                                         Porcine Small Intestine Submucosa:                     Miklos, ‘‘Single-Incision Vaginal
                                                       MedicalDevicesAdvisoryCommittee/                        Midterm Outcomes.’’ Female Pelvic                      Approach To Treat Cystocele and Vault
                                                       ObstetricsandGynecologyDevices/                         Medicine & Reconstructive Surgery 17(4):               Prolapse With an Anterior Wall Mesh
                                                       UCM275061.pdf.                                          174–179, 2011.                                         Anchored Apically to the Sacrospinous
                                                  2. Deprest, J., D. de Ridder, J.P. Roovers, et          15. Abed, H., D. D. Rahn, L. Lowenstein, et                 Ligaments.’’ International Urogynecology
                                                       al., ‘‘Medium Term Outcome of                           al., ‘‘Incidence and Management of Graft               Journal 23(1): 85–91, 2012.
                                                       Laparoscopic Sacrocolpopexy With                        Erosion, Wound Granulation, and                   28. Gustapane, S., M. Leombroni, E. Falo, et
                                                       Xenografts Compared to Synthetic                        Dyspareunia Following Vaginal Prolapse                 al., ‘‘Surgical Repair of Pelvic Organ
                                                       Grafts.’’ Journal of Urology 182: 2362–                 Repair With Graft Materials: A                         Prolapse and Follow-Up: An
                                                       2368, 2009.                                             Systematic Review.’’ International                     Institutional Multi-Center Experience.’’
                                                  3. Jeffery, S.T . and A. Nieuwoudt, ‘‘Beyond                 Urogynecology Journal 22:789–798,                      World Journal of Obstetrics and
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                                                       the Complications: Medium-Term                          2011.                                                  Gynecology 2(4): 176–180, 2013.
                                                       Anatomical, Sexual and Functional                  16. ‘‘Update on Serious Complications                  29. Sirls, L. T., G. P. McLennan, K. A.
                                                       Outcomes Following Removal of Trocar-                   Associated With Transvaginal Placement                 Killinger, et al., ‘‘Exploring Predictors of
                                                       Guided Transvaginal Mesh. A                             of Surgical Mesh for Pelvic Organ                      Mesh Eexposure After Vaginal Prolapse
                                                       Retrospective Cohort Study.’’                           Prolapse: FDA Safety Communication,’’                  Repair.’’ Female Pelvic Medicine &
                                                       International Urogynecology Journal                     issued on July 13, 2011. Available at                  Reconstructive Surgery 19(4): 206–209,
                                                       23(10): 1391–1396, 2012.                                http://www.fda.gov/MedicalDevices/                     2013.
                                                  4. Ellis, C. N., ‘‘Outcomes After the Repair of              Safety/AlertsandNotices/                          30. Sinhal, D., J. Iyer, M. Mous, et al.,
                                                       Rectoceles With Transperineal Insertion                 ucm262435.htm.                                         ‘‘Anterior-Apical Mesh Repair System in



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                                                                      Federal Register / Vol. 81, No. 2 / Tuesday, January 5, 2016 / Rules and Regulations                                                    361

                                                       an Ambulatory Setting.’’ Ambulatory                PART 884—OBSTETRICAL AND                               floor. This device is a porous implant
                                                       Surgery 19(4): 130–133, 2013.                      GYNECOLOGICAL DEVICES                                  that is made of synthetic material, non-
                                                  31. Brennand, E. A., D. Bhayana, S. Tang, et
                                                                                                                                                                 synthetic material, or a combination of
                                                       al., ‘‘Anchor Placement and Subsequent             ■ 1. The authority citation for 21 CFR
                                                       Movement in a Mesh Kit With Self-                                                                         synthetic and non-synthetic materials.
                                                                                                          part 884 continues to read as follows:                 This device does not include surgical
                                                       Fixating Tips: 6-Month Follow-Up of a
                                                       Prospective Cohort.’’ British Journal of             Authority: 21 U.S.C. 351, 360, 360c, 360e,           mesh for other intended uses
                                                       Obstetrics and Gynaecology;                        360j, 371.                                             (§ 878.3300 of this chapter).
                                                       DOI:10.1111/1471–0528.12536, 2014.                 ■ 2. Add § 884.5980 to subpart F to read                  (b) Classification. Class III (premarket
                                                  List of Subjects in 21 CFR Part 884                     as follows:                                            approval).
                                                    Medical devices.                                      § 884.5980 Surgical mesh for transvaginal                Dated: December 30, 2015.
                                                    Therefore, under the Federal Food,                    pelvic organ prolapse repair.                          Leslie Kux,
                                                  Drug, and Cosmetic Act and under                           (a) Identification. Surgical mesh for               Associate Commissioner for Policy.
                                                  authority delegated to the Commissioner                 transvaginal pelvic organ prolapse                     [FR Doc. 2015–33165 Filed 1–4–16; 8:45 am]
                                                  of Food and Drugs, 21 CFR part 884 is                   repair is a prescription device intended
                                                                                                                                                                 BILLING CODE 4164–01–P
                                                  amended as follows:                                     to reinforce soft tissue in the pelvic
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Document Created: 2016-01-05 01:46:28
Document Modified: 2016-01-05 01:46:28
CategoryRegulatory Information
CollectionFederal Register
sudoc ClassAE 2.7:
GS 4.107:
AE 2.106:
PublisherOffice of the Federal Register, National Archives and Records Administration
SectionRules and Regulations
ActionFinal order.
DatesThis order is effective on January 5, 2016.
ContactSharon Andrews, Center for Devices and Radiological Health, 10903 New Hampshire Ave., Bldg. 66, Rm. G110, Silver Spring, MD 20993, 301-796-6529, [email protected]
FR Citation81 FR 353 

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