Document ID: FDA-2014-N-0298-0004
Agency: fda
Document Type: Rule
Title: Effective Date of Requirement for Premarket Approval for Surgical Mesh
for Transvaginal Pelvic Organ Prolapse Repair
Posted Date: 2016-01-05T05:00Z

[Federal Register Volume 81, Number 2 (Tuesday, January 5, 2016)]
[Rules and Regulations]
[Pages 363-370]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-33163]

[[Page 363]]

Vol. 81

Tuesday,

No. 2

January 5, 2016

Part IV

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 884

 Effective Date of Requirement for Premarket Approval for Surgical Mesh 
for Transvaginal Pelvic Organ Prolapse Repair; Final Rule

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

[[Page 364]]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 884

[Docket No. FDA-2014-N-0298]

Effective Date of Requirement for Premarket Approval for 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 require the filing of a premarket approval 
application (PMA) or notice of completion of a product development 
protocol (PDP) for surgical mesh for transvaginal pelvic organ prolapse 
(POP) repair.

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

FOR FURTHER INFORMATION CONTACT: Sharon Andrews, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. G110, Silver Spring, MD 20993, 301-796-6529, 
sharon.andrews@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as 
amended, establishes 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.
    A preamendments device that has been classified into class III and 
devices found substantially equivalent by means of premarket 
notification (section 510(k) of the FD&C Act (21 U.S.C. 360(k)) 
procedures to such a preamendments device or to a device within that 
type (both the preamendments and substantially equivalent devices are 
referred to as preamendments class III devices) may be marketed without 
submission of a PMA until FDA issues a final order under section 515(b) 
of the FD&C Act (21 U.S.C. 360e(b)) requiring premarket approval. 
Section 515(b)(1) of the FD&C Act directs FDA to issue an order 
requiring premarket approval for a preamendments class III device.
    Under section 515(f) of the FD&C Act, the manufacturer of a 
preamendments class III device may comply with a call for PMAs by 
filing a PMA or notice of completion of a PDP. In practice, however, 
the option of filing a notice of completion of a PDP has rarely been 
used. For simplicity, although the PDP option remains available to 
manufacturers in response to a final order under section 515(b) of the 
FD&C Act, this document will refer only to the requirement for the 
filing and obtaining approval of a PMA.
    On July 9, 2012, the Food and Drug Administration Safety and 
Innovation Act (FDASIA) (Pub. L. 112-144) was enacted. Section 608(b) 
of FDASIA amended section 515(b) of the FD&C Act, changing the process 
for requiring premarket approval for a preamendments class III device 
from rulemaking to an administrative order.
    Section 515(b)(1) of the FD&C Act sets forth the process for 
issuing a final order requiring premarket approval. Specifically, prior 
to the issuance of a final order requiring premarket approval for a 
preamendments class III device, the following must occur: (1) 
Publication of a proposed order in the Federal Register; (2) a meeting 
of a device classification panel described in section 513(b) of the 
FD&C Act; and (3) consideration of comments from all affected 
stakeholders, including patients, payors, and providers. FDA published 
a proposed order to require PMAs for surgical mesh for transvaginal POP 
repair in the Federal Register of May 1, 2014 (79 FR 24642), and 
convened a meeting of a device classification panel (the ``Panel'') as 
discussed in the proposed order preamble and in this document. FDA 
received and has considered approximately 25 comments on this proposed 
order, as discussed in section III.
    Section 515(b)(3) of the FD&C Act provides that FDA shall, after 
the close of the comment period on the proposed order, consideration of 
any comments received, and a meeting of a device classification panel 
described in section 513(b) of the FD&C Act, issue a final order to 
require premarket approval or publish a document terminating the 
proceeding together with the reasons for such termination.
    A preamendments class III device may be commercially distributed 
without a PMA until 90 days after FDA issues a final order (a final 
rule issued under section 515(b) of the FD&C Act prior to the enactment 
of FDASIA is considered to be a final order for purposes of section 
501(f) of the FD&C Act (21 U.S.C. 351(f))) requiring premarket approval 
for the device, or 30 months after final classification of the device 
under section 513 of the FD&C Act, whichever is later. For surgical 
mesh for transvaginal POP repair, the later of these two time periods 
is 30 months after final classification of the device.
    Therefore, section 501(f)(2)(B) of the FD&C Act requires that a PMA 
for such devices be filed by the last day of the 30th calendar month 
following the effective date of the final order to reclassify these 
devices into class III. If a PMA is not filed by this date, then the 
device would be deemed adulterated under section 501(f) of the FD&C 
Act.
    Also, a preamendments device subject to the order process under 
section 515(b) of the FD&C Act is not required to have an approved 
investigational device exemption (IDE) (see part 812 (21 CFR part 812)) 
contemporaneous with its interstate distribution until the date 
identified by FDA in the final order requiring the filing of a PMA for 
the device. At that time, an IDE is required only if a PMA has not been 
filed. If the manufacturer, importer, or other sponsor of the device 
submits an IDE application and FDA approves it, the device may be 
distributed for investigational use. If a PMA is not filed by the later 
of the two dates, and the device is not distributed for investigational 
use under an IDE, the device is deemed to be adulterated within the 
meaning of section 501(f)(1)(A) of the FD&C Act, and subject to seizure 
and condemnation under section 304 of the FD&C Act (21 U.S.C. 334) if 
its distribution continues. Other enforcement actions include, but are 
not limited to, the following: Shipment of devices in interstate 
commerce may be subject to injunction under section 302 of the FD&C Act 
(21 U.S.C. 332), and the individuals responsible for such shipment may 
be subject to prosecution under section 303 of the FD&C Act (21 U.S.C. 
333). FDA requests that manufacturers take action

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to prevent the further use of devices for which no PMA has been filed.

II. Regulatory History of the Device

    Surgical mesh is a preamendments device, which was classified into 
class II (Sec.  878.3300 (21 CFR 878.3300)) in 1988. Beginning in 1992, 
FDA cleared premarket notification (510(k)) submissions for surgical 
mesh indicated for POP repair under the general surgical mesh 
classification regulation (Sec.  878.3300). FDA has cleared over 100 
510(k) submissions for surgical mesh with a POP repair indication.
    In September 2011, FDA held a meeting of a device classification 
panel described in section 513(b) of the FD&C Act with respect to 
surgical mesh for transvaginal POP repair (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, vaginal placement of surgical mesh 
for 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 indicated 
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 Panel meeting that would provide a basis for 
a different recommendation or findings. FDA published proposed orders 
to reclassify surgical mesh for transvaginal POP repair from class II 
to class III (the 513(e) proposed order) and to require the filing of a 
PMA if the reclassification is finalized (the 515(b) proposed order) in 
the Federal Register of May 1, 2014 (79 FR 24634; 79 FR 24642). 
Elsewhere in this issue of the Federal Register, FDA is issuing a final 
order to reclassify these devices from class II to class III.

III. Public Comments in Response to the Proposed Order

    In response to the 515(b) proposed order, FDA received 26 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) Nine comments were received from individuals or family 
members of individuals who underwent mesh repair for POP and/or stress 
urinary incontinence (SUI) and reported complications or adverse events 
experienced during or after their procedures. The complications and 
adverse events reported including organ perforation, mesh exposure, or 
extrusion into the vagina and/or visceral organs (in some cases 
requiring additional surgery), chronic pain, infection, lack of 
mobility, painful sexual intercourse, self-catheterization, recurrent 
prolapse and/or incontinence, blood loss during surgery (in some cases 
requiring transfusion), nerve damage, need for mesh removal and/or 
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 and 
SUI. The complications and adverse events reported by these commenters 
are consistent with those addressed in the 513(e) and 515(b) proposed 
order preambles, and discussed at the 2011 meeting of the Panel. The 
comments did not identify any adverse event information that was not 
already considered by FDA and the Panel.
    (Comment 2) Thirteen 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 are outside the scope of the proposed order and this final 
order. As stated in the 513(e) proposed order preamble, ``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) Eight 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 indicated 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.
    As stated earlier in this document, FDA issued a proposed order (79 
FR 24642) under section 515(b) of the FD&C Act to require the filing of 
PMAs for these devices following reclassification, which would require 
an individual demonstration of a reasonable assurance of safety and 
effectiveness for surgical mesh for transvaginal POP repair. In the 
515(b) proposed order preamble, FDA recognized the recommendations from 
the Panel that additional work should be focused on patient labeling 
and providing patients with benefit-risk information on available 
treatment options for POP, including surgical and nonsurgical options, 
so patients understand potential long-term safety and effectiveness 
outcomes. In the 515(b) proposed order, FDA tentatively asserted that 
it expects PMAs for these devices to include professional and patient 
labeling, and that the patient labeling include, among other things, 
the risks and benefits of the device and all available treatment 
options. These findings are adopted, in part, in the final order (see 
section IV, ``The Final Order'').
    Therefore, FDA does not believe that 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

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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 that there is sufficient evidence at this 
time to support a mandatory recall of this device. Under section 
518(e)(1) of the FD&C Act (21 U.S.C. 360h(e)(1)) 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 a reasonable assurance of safety and 
effectiveness of surgical mesh for transvaginal POP repair based on 
valid scientific evidence.
    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 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.
    FDA will consider other regulatory actions relating to this device 
as appropriate in the future.
    (Comment 4) Two comments were related to the need for testing prior 
to marketing, including an evaluation of the polypropylene material 
used to fabricate surgical mesh. One commenter stated that 
polypropylene material is inappropriate for implantation.
    (Response) FDA believes that a thorough evaluation of the material 
used to fabricate the surgical mesh is needed to provide a reasonable 
assurance of safety and effectiveness of the device. FDA discussed in 
the 515(b) proposed order preamble information that should be submitted 
in a PMA to address these issues. FDA is adopting these findings, in 
part, in the final order (see section IV, ``The Final Order'').
    Specifically, in the proposed order, FDA stated that manufacturers 
should provide biocompatibility, preclinical bench testing and 
preclinical animal studies, among other 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 proposed order preamble also states 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. FDA is adopting these findings in the final 
order (see section IV, ``The Final Order'').
    (Comment 5) Two comments were related to the timeline for requiring 
PMAs and requested that the requirement for premarket approval be 
immediately implemented. One commenter requested that the PMA 
requirement be retroactively applied to devices currently on the 
market.
    (Response) Section 501(f)(2)(B) of the FD&C Act outlines the 
timeframe in which a PMA must be filed by manufacturers of currently 
marketed devices that are subject to a 515(b) order for the 
manufacturers to continue legally marketing their device. For devices 
subject to a 515(b) order, the provision states that a PMA must be 
submitted by the 90th day after the date the order to require PMAs is 
issued or the last day of the 30th calendar month beginning after the 
month in which the classification in class III becomes effective, 
whichever occurs later. For surgical mesh for transvaginal POP repair, 
the later of these two time periods is 30 months after final 
classification of the device. FDA must abide by the timeframe outlined 
in the FD&C Act, and therefore may not require manufacturers of devices 
subject to the final order to submit a PMA immediately.
    (Comment 6) One comment suggested that the timeframe for filing a 
PMA (within 30 months of the final reclassification) may not allow for 
adequate patient followup of ongoing clinical studies and requested 
that FDA consider the current status of clinical studies that may be 
used to support PMA submission.
    (Response) FDA has carefully considered the current status of 
ongoing clinical studies of currently marketed surgical mesh for 
transvaginal POP repair, including studies being conducted in response 
to FDA postmarket surveillance study orders issued starting on January 
3, 2012, under section 522 of the FD&C Act (21 U.S.C. 360l), and has 
concluded that the statutory timeframe for filing a PMA (the last day 
of the 30th calendar month beginning after the month in which the 
classification in class III becomes effective) is appropriate to allow 
adequate patient followup of ongoing clinical studies. In the 515(b) 
proposed order preamble, FDA stated the expectation that ``[a]t least 1 
year of outcome data should be provided in the PMA and an additional 2-
4 years of followup should be conducted postmarket.'' FDA believes it 
is reasonable to expect that a manufacturer of surgical mesh who is 
subject to a section 522 postmarket surveillance study order issued in 
2012 or 2013 will be able to collect 1 year of outcome data within 30 
months of the final reclassification.
    (Comment 7) One comment addressed FDA's ability to review a PMA 
submitted for surgical mesh for transvaginal POP repair within 180 
days. The comment stated that a 180-day PMA review commitment may not

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be attainable and the timeline does not allow for panel review. The 
commenter requested clarification regarding what actions will be taken 
should the PMA not be approved within the 180-day review period.
    (Response) Under section 515(d)(1)(A) of the FD&C Act, unless an 
exception applies, FDA must either issue an order approving or deny 
approval of a PMA within 180 days after receipt of a PMA. FDA can 
provide an extension for review when a major amendment is submitted by 
the applicant or requested by FDA (21 CFR 814.37(c)(1)). The extended 
time period for submitting an amendment allows for, among other things, 
additional time for panel review of specific device data. Generally, a 
major amendment includes a previously unreported study, significant 
updated data from a previously reported study, detailed new analyses of 
previously submitted data, or required information previously omitted.
    FDA intends to review any submitted PMA for this device type within 
the required timeframe. As soon as it completes its review of a PMA, 
FDA will issue an approval order (Sec.  814.45(d) (21 CFR 814.45(d))), 
an approvable letter (Sec.  814.45(e)), a not approvable letter (Sec.  
814.45(e)), or an order denying approval (Sec.  814.45(a)). FDA 
strongly encourages manufacturers to meet with the Agency early through 
the presubmission program for any assistance in preparation of their 
PMA to help to expedite the PMA review process.
    (Comment 8) One comment questioned FDA's reviewing urogynecologic 
surgical mesh instrumentation in a PMA if the instrumentation is 
packaged with the surgical mesh versus reviewing instrumentation in a 
510(k) notification if the instrumentation is packaged separately from 
the surgical mesh. The commenter stated that the regulatory 
requirements for instrumentation should be based on indication and not 
its packaging configuration.
    (Response) FDA agrees that the regulatory requirements for 
urogynecological surgical mesh instrumentation should be based upon the 
indications for use of the instruments and the risk of the 
instrumentation when used as intended. Based on the indications for use 
and the risks posed by these devices, in the 515(e) proposed order, FDA 
proposed to reclassify these devices from class I to class II and 
establish special controls. FDA is not finalizing this proposed 
reclassification and special controls at this time. On February 26, 
2016, FDA will convene a panel to discuss these devices prior to 
finalizing their reclassification. These devices are currently 
classified as class I under (21 CFR 876.4730) (Manual gastroenterology-
urology surgical instrument and accessories) and may be legally 
marketed without premarket review, but would require 510(k) 
notification if the proposed reclassification of the devices is 
finalized.
    When these devices and surgical mesh for transvaginal POP repair 
are packaged together, after 510(k) notification is required for the 
instrumentation, manufacturers may wish to include both products in a 
PMA for convenience. Manufacturers are permitted but not required to do 
so. If such instrumentation is included in a PMA, FDA is clarifying 
that information regarding the manufacturing process of the 
instrumentation does not need to be submitted in a premarket 
submission, as previously stated in the 515(b) proposed order preamble 
(see section IV, ``The Final Order'').
    (Comment 9) One comment related to the types of bench testing FDA 
outlined in the 515(b) proposed order that should be included in a PMA 
and whether the various type of tests apply to all mesh types. For 
example, the commenter noted that many currently marketed surgical 
meshes indicated for transvaginal POP repair use integrated anchors or 
are self-fixating and do not utilize sutures; therefore suture pullout 
strength, which was identified in the 515(b) proposed order as a mesh 
characteristic that should be evaluated, would not be a relevant 
performance specification for these types of meshes. The commenter 
requested that FDA allow manufacturers to include a justification as to 
why certain testing is not relevant to performance specifications of a 
particular device design.
    (Response) FDA recognizes that the data required to support 
premarket approval may vary by device. In the 515(b) proposed order 
preamble, FDA identified the information that should be included in a 
PMA to provide a reasonable assurance of safety and effectiveness of 
surgical mesh for transvaginal POP repair, including evaluation of 
specific mechanical characteristics. FDA agrees that manufacturers 
should be allowed to justify why specific tests are not relevant to 
their specific mesh design in lieu of testing. As noted in the 515(b) 
proposed order preamble, FDA strongly encourages manufacturers to meet 
with the Agency early through the presubmission program for any 
assistance in preparation of their PMA.
    (Comment 10) One comment related to FDA's expectations regarding 
biocompatibility and preclinical animal study evaluation. The commenter 
requested clarification regarding why FDA recommended conducting 
biocompatibility testing prior to initiation of animal studies. The 
commenter also noted that in the 515(b) proposed order, FDA identified 
a biocompatibility test (haemocompatibility), which is not outlined in 
the Center for Devices and Radiological Health (CDRH) Blue Book Memo 
#G-95-1--``Use of International Standard ISO-10993, `Biological 
Evaluation of Medical Devices Part 1: Evaluation and Testing,' '' as a 
test for consideration for a permanent implant with tissue/bone 
contact. The commenter seeks clarity regarding the specific 
biocompatibility testing FDA believes should be conducted and a 
rationale for any testing not outlined in the Blue Book Memo.
    (Response) The biocompatibility testing outlined in the 515(b) 
proposed order preamble is consistent with that recommended in the FDA 
guidance document ``Guidance for Industry and/or for FDA Reviewers/
Staff and/or Compliance: Guidance for the Preparation of a Premarket 
Notification Application for a Surgical Mesh'' issued on March 2, 1999 
(Ref. 2). There are two biocompatibility studies recommended in the 
guidance document (and the 515(b) proposed order) that are not included 
in CDRH's Blue Book Memorandum #G95-1--``Use of International Standard 
ISO-10993, `Biological Evaluation of Medical Devices Part 1: Evaluation 
and Testing,' '' dated May 1, 1995 (Ref. 3)--pyrogenicity and 
hemolysis. FDA recommended pyrogenicity testing to help protect 
patients from the risk of febrile reaction (Ref. 4). FDA recommended 
hemolysis testing on surgical mesh for transvaginal POP repair because 
red blood lysis in the surgical field may adversely affect the healing 
process.
    FDA generally recommends that biocompatibility testing be completed 
prior to preclinical animal study evaluation to ensure that the 
preclinical animal study evaluation results are valid and can be used 
to support the final device design. If biocompatibility testing and the 
preclinical animal study evaluation are conducted simultaneously and 
biocompatibility testing results are problematic or identify a safety 
concern resulting in changes to the device design or materials, the 
preclinical animal study evaluation may need to be repeated. In 
addition, the results of biocompatibility

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testing may prompt the need for additional preclinical evaluation. As 
noted in the 515(b) proposed order preamble, FDA strongly encourages 
manufacturers to meet with the Agency early through the presubmission 
program for any assistance in preparation of their PMA.
    (Comment 11) One comment stated that the preclinical animal study 
requirements outlined in the 515(b) proposed order are not clearly 
defined and requested that FDA provide additional information on study 
design and animal model selection as well as the risks that are 
intended to be mitigated by the proposed animal study.
    (Response) Preclinical animal studies are intended to evaluate the 
safety of the device, specifically the local and systemic effects of 
the device. Preclinical animal studies may not be needed to evaluate 
all surgical mesh for transvaginal POP repair; however, preclinical 
animal studies may be appropriate in some situations, for example, to 
evaluate a new mesh material or characterize the resorption rate of a 
resorbable surgical mesh product. FDA strongly encourages manufacturers 
to meet with the Agency early through the presubmission program to 
receive feedback regarding the need for preclinical animal studies, 
study design, and animal model selection to evaluate a specific 
surgical mesh for transvaginal POP repair.
    (Comment 12) One comment stated that the use of postmarket 
surveillance studies to fulfill clinical requirements for the PMA 
creates confusion regarding how such a study can have two purposes 
(postmarket surveillance and PMA approval) without compromising the 
study design and statistical rigor of the study. The comment also 
stated that the 5-year followup implied in the 515(b) proposed order is 
not in line with 3-year followup requested in the postmarket 
surveillance orders.
    (Response) In the 515(b) proposed order preamble, FDA outlined 
expectations for data collection, safety and effectiveness outcomes, 
and study followup. FDA noted that we intend to consider proposals for 
different study designs and will decide on a case-by-case basis whether 
each proposed study design is likely to generate data adequate to 
support a PMA (79 FR 24642 at 24647). In addition, we noted that FDA 
intends to consider the use of study data collected by manufacturers in 
response to FDA issued postmarket surveillance study orders (79 FR 
24642 at 24647). FDA believes that data from the section 522 postmarket 
surveillance studies may be able to fulfill the clinical requirements 
to support PMA approval--in addition to fulfilling the regulatory 
requirements of the orders issued under section 522 of the FD&C Act--if 
appropriately designed. However, as noted in the 515(b) proposed order 
preamble, FDA strongly encourages manufacturers to meet with the Agency 
to discuss specific proposals utilizing the presubmission program.
    In addition, FDA noted the following in the postmarket surveillance 
orders issued under section 522 of the FD&C Act: ``Although FDA has not 
come to a final decision on reclassification, you may wish to consider 
the data requirements for a PMA in deciding the design of your 522 
study. If you are interested in utilizing data collected to fulfill 
this 522 order to also fulfill a possible future PMA, we suggest you 
indicate your interest on the cover letter of your 522 study plan and 
discuss with FDA possible 522 study designs that may be sufficient to 
support a PMA application.'' For those manufacturers who indicated 
interest in using a 522 study to support a future PMA, FDA's review of 
their 522 protocol assessed both the requirements of the 522 order and 
the ability to generate sufficient data to support premarket approval.
    FDA also notes that the 522 orders requested collection of safety 
and effectiveness outcomes for surgical mesh for transvaginal POP 
repair at 6 months, 12 months, 18 months, 24 months, and 36 months 
following surgery. Therefore, FDA expects that the 522 studies should 
be designed to collect the 1-year outcomes requested to support 
premarket approval. FDA acknowledges that the 522 orders requested 3-
year followup. However, FDA notes that based on its detailed review of 
the information provided in a PMA, we may request additional postmarket 
followup.
    (Comment 13) One comment stated that FDA's expectation, set forth 
in the 515(b) proposed order, that patient labeling include a notice of 
availability of an FDA Safety Communication could be ``conflicting'' 
and lead to confusion because it is unclear how a reference to this 
communication would be appropriate for a device with an approved PMA 
establishing its safety and effectiveness. The commenter stated that 
the patient labeling should be focused on the benefit-risk profile of 
each product as established in the related PMA and requested that FDA 
consider alternative methods for providing the information found in the 
FDA communication to patients.
    (Response) FDA agrees that patient labeling should be reflective of 
the risks and benefits of individual devices. FDA also believes that 
there is important, relevant information in FDA's Safety Communication 
that may be helpful to patients even after PMAs are approved for this 
device type (Ref. 5). For example, the Safety Communication included 
information regarding the potential risks of surgical mesh for 
transvaginal POP repair, nonsurgical options, and recommended questions 
that patients should ask their surgeon, which may be relevant even 
after PMAs are approved for this device type. However, FDA acknowledges 
that including the notice of availability of the Safety Communication 
may not be the best way to provide patients with the relevant 
information. As a result, FDA is revising this expectation and is now 
recommending that patient labeling include relevant information from 
FDA's Safety Communication and/or FDA's Urogynecologic Surgical Mesh 
Implants Web page (Ref. 6), including but not limited to, recommended 
patient questions for their surgeon, FDA activities related to surgical 
mesh for transvaginal POP repair, and FDA contact information.
    To help ensure that patients are adequately informed, FDA also 
recommends that a link to FDA's Urogynecologic Surgical Mesh Implants 
Web page be included in the patient labeling because it provides timely 
and transparent information to the public, including appropriate 
stakeholders and patients.
    (Comment 14) One comment regarding the patient identification card 
discussed in the 515(b) proposed order noted that the card can be 
easily provided by the manufacturer, compliance with use of the card is 
dependent on the implanting physician, and should not lead to followup 
activities for the manufacturer.
    (Response) FDA recognizes that a successful identification system 
requires support from parties other than the manufacturer, such as the 
implanting physician and patient. FDA's expectation, as set forth in 
the 515(b) proposed order preamble, was that patient labeling include a 
patient identification card, which would be initially provided by the 
manufacturer. FDA does not anticipate further followup actions by the 
manufacturer. These findings are adopted, in part, in the final order 
(see section IV, ``The Final Order'').

IV. The Final Order

    Under section 515(b)(3) of the FD&C Act, FDA is adopting its 
findings, in part, as published in the preamble of the 515(b) proposed 
order (79 FR 24642) and issuing this final order to require the filing 
of a PMA for surgical mesh for

[[Page 369]]

transvaginal POP repair. As discussed in this document, FDA is amending 
certain previous findings. The Agency now finds that: (1) Manufacturing 
process information of the specialized instrumentation should not be 
included in a premarket submission and (2) patient labeling should 
include relevant information from FDA's Safety Communication and/or 
FDA's Urogynecologic Surgical Mesh Implants Web page rather than the 
notice of availability of FDA's Safety Communication. The patient 
labeling should also include a link to the FDA's Urogynecologic 
Surgical Mesh Implants Web page. This final order will revise 21 CFR 
part 884.
    Under the final order, a PMA for surgical mesh for transvaginal POP 
repair is required to be filed on or before July 5, 2018, for any 
preamendments class III devices that were in commercial distribution 
before May 28, 1976, or that has been found by FDA to be substantially 
equivalent to such a device on or before July 5, 2018. Any other device 
subject to this order is required to have an approved PMA in effect 
before it may be marketed.
    If a PMA for any of the preamendments class III devices subject to 
this order is not filed by this date, that device will be deemed 
adulterated under section 501(f)(1)(A) of the FD&C Act, and commercial 
distribution of the device must cease immediately.
    The device may, however, be distributed for investigational use, if 
the applicable requirements of the IDE regulations (part 812), 
including obtaining IDE approval, are met on or before 30 months after 
the effective date of this order. There will be no extended period for 
filing an IDE, nor exemption from the IDE requirements (see Sec.  
812.2(d)), and studies may not be initiated without appropriate IDE 
approvals, as required.

V. 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.

VI. 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 807, subpart E, have 
been approved under OMB control number 0910-0120; the collections of 
information in 21 CFR part 814, subpart B, have been approved under OMB 
control number 0910-0231; the collections of information in part 812 
have been approved under OMB control number 0910-0078; the collections 
of information under 21 CFR 822 have been approved under OMB control 
number 0910-0449; and the collections of information under 21 CFR 801 
have been approved under OMB control number 0910-0485.

VII. Codification of Orders

    Prior to the amendments by FDASIA, section 515(b) of the FD&C Act 
provided for FDA to issue regulations to require PMA approval for 
preamendments devices or devices found substantially equivalent to 
preamendments devices. Section 515(b) of the FD&C Act, as amended by 
FDASIA, provides for FDA to require PMA approval for such devices by 
issuing a final order following the issuance of a proposed order in the 
Federal Register. FDA will continue to codify the requirement for a PMA 
approval in the Code of Federal Regulations. Therefore, under section 
515(b)(1)(A) of the FD&C Act, as amended by FDASIA, in this final 
order, we are requiring PMA approval for surgical mesh for transvaginal 
POP repair and we are making the language in 21 CFR 884.5980 consistent 
with this final order.

VIII. 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. FDA Meeting of the Obstetrics & Gynecological Devices Panel, 
September 8-9, 2011. Available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ObstetricsandGynecologyDevices/ucm262488.htm.
2. ``Guidance for Industry and/or for FDA Reviewers/Staff and/or 
Compliance: Guidance for the Preparation of a Premarket Notification 
Application for a Surgical Mesh'' issued on March 2, 1999. Available 
at http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073791.pdf.
3. Blue Book Memorandum #G95-1--''Use of International Standard ISO-
10993, 'Biological Evaluation of Medical Devices Part 1: Evaluation 
and Testing' '' issued on May 1, 1995. Available at http://www.fda.gov/RegulatoryInformation/Guidances/ucm080735.htm.
4. ``Guidance for Industry Pyrogen and Endotoxins Testing: Questions 
and Answers,'' June 2012. Available at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm310098.pdf.
5. ``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.
6. FDA's Urogynecologic Surgical Mesh Implants Web page. Available 
at http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/ImplantsandProsthetics/UroGynSurgicalMesh/default.htm.

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 paragraph (c) to Sec.  884.5980 to read as follows:

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

* * * * *
    (c) Date premarket application approval or notice of completion of 
a product development protocol is required. A premarket application 
approval or notice of completion of a product development protocol for 
a device is required to be filed with the Food and Drug Administration 
on or before July 5, 2018, for any surgical mesh described in paragraph 
(a) of this section that was in commercial distribution before May 28, 
1976, or that has, on or before July 5, 2018, been found substantially 
equivalent to a surgical mesh described in paragraph (a) of this 
section that was in commercial distribution before May 28, 1976. Any 
other surgical mesh for transvaginal

[[Page 370]]

pelvic organ prolapse repair shall have an approved premarket 
application or declared completed product development protocol in 
effect before being placed in commercial distribution.

    Dated: December 30, 2015.
Leslie Kux,
Associate Commissioner for Policy.
[FR Doc. 2015-33163 Filed 1-4-16; 8:45 am]
 BILLING CODE 4164-01-P