[Federal Register Volume 79, Number 84 (Thursday, May 1, 2014)]
[Proposed Rules]
[Pages 24642-24648]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2014-09909]


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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: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is 
issuing a proposed administrative order to require the filing of a 
premarket approval application (PMA) if the surgical mesh for 
transvaginal pelvic organ prolapse (POP) repair device is reclassified 
from class II to class III. The Agency is summarizing its proposed 
findings regarding the degree of risk of illness or injury designed to 
be eliminated or reduced by requiring the device to meet the statute's 
PMA requirements and the benefit to the public from the use of the 
device.

DATES: Submit either electronic or written comments on this proposed 
order by July 30, 2014. FDA intends that, if a final order based on 
this proposed order is issued, anyone who wishes to continue to market 
the device will need to submit a PMA within 90 days of the effective 
date of the final order or on the last day of the 30th

[[Page 24643]]

calendar month beginning after the month in which the classification of 
the device in class III became effective, whichever occurs later. See 
section VI for more information about submitting a PMA. See section X 
for the effective date of any final order that may publish based on 
this proposal.

ADDRESSES: You may submit comments, identified by Docket No. FDA-2014-
N-0298, by any of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     Mail/Hand delivery/Courier (for paper submissions): 
Division of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the Agency name 
and Docket No. FDA-2014-N-0298 for this rulemaking. All comments 
received may be posted without change to http://www.regulations.gov, 
including any personal information provided. For additional information 
on submitting comments, see the ``Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts and/or go to the Division of 
Dockets Management, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Melissa Burns, Center for Devices and 
Radiological Health, Food and Drug Administration, 10903 New Hampshire 
Ave., Bldg. 66, Rm. 1646, Silver Spring, MD 20993, 301-796-5616, 
melissa.burns@fda.hhs.gov.

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (the FD&C Act), as amended 
by the Medical Device Amendments of 1976 (the 1976 amendments) (Pub. L. 
94-295), the Safe Medical Devices Act of 1990 (Pub. L. 101-629), the 
Food and Drug Administration Modernization Act of 1997 (Pub. L. 105-
115), the Medical Device User Fee and Modernization Act of 2002 (Pub. 
L. 107-250), the Medical Devices Technical Corrections Act of 2004 
(Pub. L. 108-214), the Food and Drug Administration Amendments Act of 
2007 (Pub. L. 110-85), and the Food and Drug Administration Safety and 
Innovation Act (FDASIA) (Pub. L. 112-144), 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 procedures in section 510(k) of the FD&C Act (21 U.S.C. 
360(k)) 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.
    Section 515(f) of the FD&C Act provides an alternative pathway for 
meeting the premarket approval requirement. Under section 515(f), 
manufacturers may meet the premarket approval requirement if they file 
a notice of completion of a product development protocol (PDP) approved 
under section 515(f)(4) of the FD&C Act and FDA declares the PDP 
completed under section 515(f)(6)(B) of the FD&C Act. Accordingly, the 
manufacturer of a preamendments class III device may comply with a call 
for PMAs by filing a PMA or a 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 filing and obtaining approval of a PMA.
    On July 9, 2012, FDASIA 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. 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. 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. As explained 
further in section V, this device classification panel meeting 
discussed whether surgical mesh for transvaginal POP repair should be 
reclassified or remain in class II, and the discussion included whether 
PMAs should be required for these devices. The panel recommended that 
the device be reclassified into class III because general controls and 
special controls together would not be sufficient to provide reasonable 
assurance of the safety and effectiveness of the device. The panel 
consensus was that premarket clinical data are needed for surgical mesh 
for transvaginal POP repair, and that each individual mesh device 
should be evaluated against a control arm of traditional ``native 
tissue'' (non-mesh) repair to demonstrate a reasonable assurance of 
safety and effectiveness. FDA is not aware of new information that 
would provide a basis for a different recommendation or findings. 
Indeed, the additional information received since the 2011 panel 
meeting and discussed further in section V highlights the need to 
review these devices under a PMA and reinforces the recommendation and 
findings of the panel.
    Section 515(b)(2) of the FD&C Act provides that a proposed order to 
require premarket approval shall contain: (1) The proposed order, (2) 
proposed findings with respect to the degree of risk of illness or 
injury designed to be eliminated or reduced by

[[Page 24644]]

requiring the device to have an approved PMA and the benefit to the 
public from the use of the device, (3) an opportunity for the 
submission of comments on the proposed order and the proposed findings, 
and (4) an opportunity to request a change in the classification of the 
device based on new information relevant to the classification of the 
device.
    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. If FDA 
terminates the proceeding, FDA is required to initiate reclassification 
of the device under section 513(e) of the FD&C Act, unless the reason 
for termination is that the device is a banned device under section 516 
of the FD&C Act (21 U.S.C. 360f).
    A preamendments class III device may be commercially distributed 
without a PMA until 90 days after FDA issues a final order requiring 
premarket approval for the device, or 30 months after classification of 
the device in class III under section 513 of the FD&C Act becomes 
effective, whichever is later. Elsewhere in this issue of the Federal 
Register, FDA is proposing an order to reclassify surgical mesh for 
transvaginal POP repair from class II to class III. Therefore, assuming 
the reclassification order and the order to require PMAs are finalized, 
the date by which a PMA for surgical mesh for transvaginal POP repair 
must be filed will depend on the date the final reclassification order 
becomes effective and the date the final order to require PMAs is 
issued. If a PMA is not filed for such device by the later of the two 
dates specified in section 501(f)(2)(B) of the FD&C Act (21 U.S.C. 
351(f)(2)(B)) (i.e., the 90th day after the date the order to require 
PMAs is issued and the last day of the 30th calendar month beginning 
after the month in which the classification in class III becomes 
effective), then the device would be deemed adulterated under section 
501(f) of the FD&C Act unless the device is distributed for 
investigational use under an approved application for an 
investigational device exemption (IDE).
    In accordance with section 515(b) of the FD&C Act, interested 
persons are being offered the opportunity to request reclassification 
of surgical mesh for transvaginal POP repair.

II. Regulatory History of the Device

    Surgical mesh is a preamendments device classified into class II 
(Sec.  878.3300 (21 CFR 878.3300)). Beginning in 1992, FDA cleared 
premarket notification (510(k)) submissions for surgical mesh indicated 
for transvaginal 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 indication. Elsewhere 
in this issue of the Federal Register, FDA is proposing to reclassify 
this device into class III under section 513(e) of the FD&C Act.

III. Dates New Requirements Apply

    Assuming FDA finalizes the order proposing reclassification of 
surgical mesh for transvaginal POP repair this device will be 
classified into class III. In accordance with sections 501(f)(2)(B) and 
515(b) of the FD&C Act, FDA is proposing to require that a PMA be filed 
with the Agency by the last day of the 30th calendar month beginning 
after the month in which the classification of the device in class III 
became effective, or on the 90th day after the date of the issuance of 
a final order under 515(b), whichever is later. An applicant whose 
surgical mesh for transvaginal POP repair was legally in commercial 
distribution before May 28, 1976, or whose surgical mesh for 
transvaginal POP repair has been found to be substantially equivalent 
prior to the issuance of a final order under section 515(b), will be 
permitted to continue marketing such class III device during FDA's 
review of the PMA, provided that a PMA is timely filed. FDA intends to 
review any PMA for the device within 180 days. FDA cautions that, under 
section 515(d)(1)(B)(i) of the FD&C Act, the Agency may not enter into 
an agreement to extend the review period for a PMA beyond 180 days 
unless the Agency finds that ``. . . the continued availability of the 
device is necessary for the public health.''
    FDA intends that, under Sec.  812.2(d) (21 CFR 812.2(d)), the 
publication in the Federal Register of any final order based on this 
proposal will include a statement that, as of the date on which the 
filing of a PMA is required, the exemptions in Sec.  812.2(c)(1) and 
(2) from the requirements of the IDE regulations for preamendments 
class III devices will cease to apply to any device that is subject to 
the final order and that is: (1) Not legally on the market on or before 
that date or (2) legally on the market on or before that date but for 
which a PMA is not filed by that date, or for which PMA approval has 
been denied or withdrawn.
    If a PMA for a class III device is not filed with FDA within 90 
days of the date of issuance of the final order requiring premarket 
approval for the device or 30 months after the classification of the 
device into class III, whichever is later, commercial distribution of 
the device must cease. The device may be distributed for 
investigational use only if the requirements of the IDE regulations in 
part 812 are met. The requirements for investigational use of 
significant risk devices include submitting an IDE application to FDA 
for review and approval. An approved IDE is required to be in effect 
before an investigation of the device may be initiated or continued 
under Sec.  812.30. FDA, therefore, recommends that IDE applications be 
submitted to FDA at least 30 days before the date a PMA is required to 
be filed to avoid interrupting investigations.

IV. Device Subject to This Proposal

    Surgical mesh for transvaginal POP repair can be placed abdominally 
or transvaginally to repair POP. When placed transvaginally, surgical 
mesh can be placed in the anterior vaginal wall to aid in the 
correction of cystocele (anterior repair), in the posterior vaginal 
wall to aid in correction of rectocele (posterior repair), or attached 
to the vaginal wall and pelvic floor ligaments to correct uterine 
prolapse or vaginal apical prolapse (apical repair). These devices are 
made of synthetic material, non-synthetic material, or a combination of 
both. They are marketed as either stand alone mesh products or mesh 
kits (i.e., the product includes mesh and instrumentation to aid 
insertion, placement, fixation, and/or anchoring).
    Elsewhere in this issue of the Federal Register, FDA is proposing 
to identify surgical mesh for transvaginal POP repair in the new Sec.  
884.5980 (21 CFR 884.5980) in the following way: Surgical mesh for 
transvaginal POP repair is a prescription device intended to reinforce 
soft tissue in the pelvic floor. This device is a porous implant that 
is synthetic, non-synthetic, or both. This device does not include 
surgical mesh for other intended uses (see Sec.  878.3300).

V. Proposed Findings With Respect to Risks and Benefits for Surgical 
Mesh for Transvaginal POP Repair

    As required by section 515(b) of the FD&C Act, FDA is publishing 
its proposed findings regarding: (1) The degree of risk of illness or 
injury designed to be eliminated or reduced by requiring that these 
devices have an

[[Page 24645]]

approved PMA and (2) the benefits to the public from the use of the 
devices.
    These findings are based on the reports and recommendations of the 
Obstetrics and Gynecological Devices Panel from the meeting on 
September 8-9, 2011, and any additional information that FDA has 
obtained. Additional information regarding the risks as well as the 
classification of this device can be found in section V.3 as well as in 
the proposed order, published elsewhere in this issue of the Federal 
Register, proposing to reclassify these devices into class III. The 
device has the potential to benefit the public by aiding in the 
correction of cystocele (anterior repair), rectocele (posterior 
repair), uterine prolapse, or vaginal apical prolapse (apical repair). 
The risks associated with the device include perioperative risks (organ 
perforation or injury and bleeding); mesh exposure; mesh extrusions; 
vaginal scarring, shrinkage, and tightening; pelvic pain; infection; de 
novo dyspareunia; de novo voiding dysfunction (e.g., incontinence); 
neuromuscular problems (including groin and leg pain); recurrent 
prolapse; and resurgery.

A. Summary of Data

    In October 2008, as a result of over 1,000 adverse events received, 
FDA issued a Public Health Notification (PHN) informing clinicians and 
their patients of the adverse event findings related to use of 
urogynecologic surgical mesh (Ref. 1). The PHN also provided 
recommendations for clinicians on how to mitigate the risks associated 
with these devices and information for their patients. On July 13, 
2011, based on an updated adverse event search, FDA issued a Safety 
Communication entitled ``UPDATE on Serious Complications Associated 
With Transvaginal Placement of Surgical Mesh for Pelvic Organ 
Prolapse'' (Ref. 2).
    The continued reports of adverse events also prompted FDA to 
consider other available information regarding the use of surgical mesh 
for transvaginal POP repair and to evaluate whether the classification 
of this device type should be reconsidered. FDA systematically 
evaluated the peer-reviewed scientific literature to revisit the 
fundamental question of the safety and effectiveness of surgical mesh 
for transvaginal POP repair. Based on its review, FDA believes that the 
rate and severity of mesh-specific adverse events following vaginal POP 
repair with mesh calls into question the safety of these devices. 
Additionally, the available scientific literature does not provide 
evidence that surgical mesh used for vaginal POP repair offers a clear 
improvement in effectiveness when compared to traditional repair. FDA's 
detailed evaluation of the scientific literature is discussed in FDA's 
executive summary for the September 8-9, 2011, panel meeting which is 
discussed further in this document (Ref. 3).
    On September 8-9, 2011, FDA convened a meeting of the Obstetrics 
and Gynecological Devices Panel (the Panel), a device classification 
panel described in section 513(b) of the FD&C Act, and referred the 
proposed reclassification of surgical mesh for transvaginal POP repair 
to the Panel for its recommendations on the proposed change in the 
device's classification from class II to class III (Ref. 4). The Panel 
consensus was that a favorable benefit-risk profile for surgical mesh 
used for transvaginal POP repair has not been well established. The 
Panel discussed the number of serious adverse events associated with 
the use of these devices and concluded that their safety is in 
question. In addition, the Panel consensus was that the effectiveness 
of surgical mesh for transvaginal POP repair has not been well 
established, and the device may not be more effective than traditional 
non-mesh surgery, especially for the apical and posterior vaginal 
compartments.
    Additionally, the Panel consensus was that premarket clinical data 
are needed for surgical mesh for transvaginal POP repair, and the 
majority of panel members recommended that each individual mesh be 
evaluated against a control arm of traditional ``native-tissue'' (non-
mesh) repair to demonstrate a reasonable assurance of safety and 
effectiveness for the device. Panel members emphasized that these 
studies should evaluate both anatomic outcomes and patient satisfaction 
and that the duration of followup should be at least 1 year, with 
additional followup in a postmarket setting.
    The Panel's consensus was that each individual mesh device needed 
to undergo a comparison to native tissue repair in order to establish a 
reasonable assurance of safety and effectiveness. The Panel also 
emphasized that additional work should be focused on patient labeling 
and informed consent, including providing patients with benefit-risk 
information on available treatment options for POP--surgical and non-
surgical options so patients understand long-term safety and 
effectiveness outcomes. Panel members also recommended mandatory 
registration of implanted devices, as well as surgeon training and 
credentialing. They encouraged FDA to work with other stakeholders, 
such as clinical professional organizations and industry, to use 
existing databases and new data collection tools (e.g., registries) to 
develop a meaningful database on postmarket clinical outcomes.

B. Risks to Health

    FDA has evaluated the risks to health associated with use of 
surgical mesh indicated for transvaginal POP repair. In doing so, FDA 
considered information from the reports and recommendations of the 
Panel meeting on September 8, 2011 (Ref. 4), the adverse event reports 
for these devices in FDA's Manufacturer and User Facility Device 
Experience Database, and the published scientific literature which is 
discussed in FDA's executive summary for the September 2011 Panel 
meeting (Ref. 3). Based on this information, FDA has identified the 
following risks:
    1. Perioperative risks: Organ perforation or injury and bleeding 
(including hemorrhage/hematoma)
    2. Vaginal mesh exposure: Clinical sequelae include pelvic pain, 
infection, de novo dyspareunia (painful sex for patient or partner), de 
novo vaginal bleeding, atypical vaginal discharge, and the need for 
additional corrective surgeries (possibly including mesh excision).
    3. Mesh extrusion (e.g., into the bladder or rectum): Clinical 
sequelae include pelvic pain, infection, de novo dyspareunia, fistula 
formation, and the need for additional corrective surgeries (possibly 
including suprapubic catheter, diverting colostomy).
    4. Other risks that can occur without mesh exposure or extrusion: 
Vaginal scarring, shrinkage, and tightening (possibly caused by mesh/
tissue contraction); pelvic pain; infection (including pelvic abscess); 
de novo dyspareunia; de novo voiding dysfunction (e.g., incontinence); 
recurrent prolapse; and neuromuscular problems (including groin and leg 
pain).

C. Benefits of the Device

    Surgical mesh for transvaginal POP repair has the potential to 
benefit the public by aiding in the correction of cystocele (anterior 
repair), rectocele (posterior repair), uterine prolapse, or vaginal 
apical prolapse (apical repair). These findings are based on the 
reports and recommendations of the Panel meeting (Ref. 4), and the 
published scientific literature, which is discussed in FDA's executive 
summary for the Panel meeting (Ref. 3).

D. Summary of FDA Findings

    FDA tentatively concludes that surgical mesh for transvaginal POP

[[Page 24646]]

repair should be reclassified from class II to class III. FDA 
tentatively agrees with the Panel's consensus that the safety and 
effectiveness of this device type has not been established. FDA 
tentatively concludes that insufficient information exists regarding 
the risks and benefits of the device in order for FDA to determine that 
general and special controls together will provide reasonable assurance 
of the safety and effectiveness of surgical mesh intended for 
transvaginal POP repair. In addition, FDA tentatively determines that 
the risks to health identified previously in this document for the use 
of surgical mesh for transvaginal POP repair, in the absence of an 
established positive benefit-risk profile, present a potential 
unreasonable risk of illness or injury. Further, because FDA 
tentatively finds that there is insufficient valid scientific evidence, 
as defined in Sec.  860.7 (21 CFR 860.7), for FDA to determine the 
probable risks and the effectiveness of the device type, FDA is 
proposing to require an individual demonstration that a reasonable 
assurance of safety and effectiveness exists for each device within 
this type. The manufacturer of each individual device will have the 
opportunity to demonstrate the safety and effectiveness of the device 
for its intended use by submitting a premarket approval application.

VI. PMA Requirements

    A PMA for surgical mesh for transvaginal POP repair would need to 
include the information required by section 515(c)(1) of the FD&C Act. 
Such a PMA should also include a detailed discussion of the risks 
identified previously, as well as a discussion of the effectiveness of 
the device for which premarket approval is sought. In addition, a PMA 
must include all data and information on the following: (1) Any risks 
known, or that should be reasonably known, to the applicant that have 
not been identified in this document; (2) the effectiveness of the 
device that is the subject of the application; and (3) full reports of 
all preclinical and clinical information from investigations on the 
safety and effectiveness of the device for which premarket approval is 
sought.
    A PMA must include valid scientific evidence to demonstrate 
reasonable assurance of the safety and effectiveness of the device for 
its intended use (see Sec.  860.7(c)(2)). Valid scientific evidence is 
evidence from well-controlled investigations, partially controlled 
studies, studies and objective trials without matched controls, well-
documented case histories conducted by qualified experts, and reports 
of significant human experience with a marketed device, from which it 
can fairly and responsibly be concluded by qualified experts that there 
is reasonable assurance of the safety and effectiveness of a device 
under its conditions of use. Isolated case reports, random experience, 
reports lacking sufficient details to permit scientific evaluation, and 
unsubstantiated opinions are not regarded as valid scientific evidence 
to show safety or effectiveness. (See Sec.  860.7(c)(2).)
    To present reasonable assurance of safety and effectiveness of 
surgical mesh for transvaginal POP repair, FDA tentatively concludes 
that manufacturers should provide the information summarized in this 
document. In addition, FDA strongly encourages manufacturers to meet 
with the Agency early through the presubmission program for any 
assistance in preparation of their PMA.

A. Indications for Use

    Manufacturers should provide indications for use statements that 
include the route of placement for the mesh (i.e., transvaginal), the 
anatomical site of repair (e.g., anterior/apical, posterior/apical, or 
total), and specify any instrumentation required for implantation.

B. Device Description

    A detailed description of the mesh design (e.g., material, material 
source, colorants) and use (i.e., mode of operation), as well as a 
brief description of the manufacturing processes, including a flowchart 
that describes how the mesh is assembled, should be provided.
    If introducer instrumentation is packaged with the mesh, then a 
detailed description of the introducer instrumentation (e.g., material, 
material source, colorants) and the manufacturing processes for the 
instrumentation should be provided. Instrumentation that is packaged 
with the mesh will be reviewed in the PMA application. Introducer 
instrumentation that is provided separately and not packaged with the 
mesh will be reviewed separately in a 510(k) notification.

C. Sterilization and Shelf Life

    Manufacturers should provide data that demonstrates that the mesh 
and the accessory introducer instrumentation retain their mechanical 
characteristics following sterilization and for the entire length of 
the intended shelf life. The mechanical characteristics for the mesh 
include at minimum: Compliance (i.e., elastic modulus), tensile 
strength, suture pullout strength, mesh arm(s) strength, burst 
strength, and tear resistance. If the introducer instrumentation 
includes a mesh-deployment mechanism, this mechanism should function 
throughout the shelf life of the device.

D. Reprocessing

    If the introducer instrumentation is intended for reuse, the 
manufacturer should provide data to validate the cleaning and 
disinfection/sterilization instructions.

E. Biocompatibility

    Manufacturers should conduct biocompatibility testing on the 
device, including the mesh implant and introducer instrumentation, to 
fully characterize its safety profile prior to initiation of animal and 
clinical studies. This includes appropriate testing as outlined in Blue 
Book Memo G-95-1 ``Use of International Standard ISO-10993, 
'Biological Evaluation of Medical Devices Part 1: Evaluation and 
Testing''' (Ref. 5) (e.g., cytotoxicity, genotoxicity, hemolysis, 
sensitization, irritation or intracutaneous reactivity, acute systemic 
toxicity, subchronic toxicity, chronic toxicity, implantation and 
materials-mediated pyrogenicity).

F. Preclinical Bench Testing

    Manufacturers should perform testing to obtain the following 
information on the mesh implant: Thickness, weave characteristics 
(i.e., woven or nonwoven), fiber type (i.e., monofilament or 
multifilament) exact pore size, density, compliance (i.e., elastic 
modulus), tensile strength, suture pullout strength, mesh arm(s) 
strength, burst strength, and tear resistance.
    For devices composed of materials from animal sources, 
manufacturers should provide information on the species and tissue from 
which the animal material was derived, details on how the health of the 
herd is maintained, and how the health of each animal is maintained. 
Furthermore, manufacturers should test for residual cellular/DNA/
protein matter on animal-derived mesh.
    For devices containing degradable/absorbable components, 
manufacturers should provide in vitro and in vivo degradation rate data 
with supporting mechanical data (as described previously) to 
demonstrate adequate strength over time.

G. Preclinical Animal Studies

    Manufacturers should conduct animal studies to evaluate in vivo 
performance of mesh in an appropriate animal model. If designed 
appropriately, these studies may also obviate the need for

[[Page 24647]]

separate implantation studies to assess biocompatibility as indicated 
previously. The animal studies should be conducted for 6 months' 
duration to evaluate shrinking and/or calcification of the mesh, 
histology of the surrounding tissue, and extraction of the mesh. In 
addition, implantation of the mesh should occur in an appropriate 
anatomic location (i.e., not a subcutaneous pocket). Complete study 
reports for all the preclinical studies should include, but not be 
limited to: (1) A prospectively designed protocol and all protocol 
amendments; (2) a detailed description of the study design (e.g., 
description of animal species/animal models, control and test articles 
used, dose levels, detailed procedures for test article administration 
and collection of all study protocol parameters); (3) results for all 
parameters evaluated for each animal in the study; and (4) the analysis 
and interpretation of the study data.

H. Premarket Clinical Studies

    FDA tentatively concludes that premarket clinical data is needed 
for all surgical mesh indicated for transvaginal POP repair to 
demonstrate a reasonable assurance of safety and effectiveness. FDA 
anticipates that these data may need to be collected in a patient- and 
evaluator-masked study that compares surgical mesh to a non-mesh 
control (i.e., traditional native tissue transvaginal repair) with 
respect to safety and effectiveness. This study should evaluate a 
clinically relevant measure(s) of effectiveness (e.g., prolapse at or 
above the hymenal ring, subjective cure, and quality of life, no 
recurrent prolapse), key safety outcomes (e.g., serious adverse events, 
defined as hospital readmission or return to operating room), urinary 
and bowel function, sexual function, etc., as outcome measures. At 
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 intends to consider proposals for different study designs that 
meet the intent of the previously mentioned list and will decide on a 
case-by-case basis whether each proposed study design is likely to 
generate data adequate to support a PMA. FDA also intends to consider 
the use of study data collected by manufacturers in response to FDA 
issued postmarket surveillance study orders issued beginning on January 
3, 2012, under section 522 of the FD&C Act (21 U.S.C. 360l) for 
transvaginal POP mesh products that are already legally marketed.

I. Professional Labeling

    FDA would expect the professional (physician) labeling to include 
the following elements:
     Indications for Use statement;
     Contraindications;
     Device description (e.g., material type, introducer 
instrumentation included, and degradation rate when applicable);
     Images of the mesh and introducer instrumentation;
     Warnings;
     Precautions;
     Adverse event rates, including:
    [cir] Perioperative risks:
    [ssquf] Organ perforation or injury;
    [ssquf] Bleeding (including hemorrhage and hematoma);
    [cir] Mesh exposure in the vagina;
    [cir] Mesh extrusion into another organ;
    [cir] Pelvic pain;
    [cir] Infection (by type);
    [cir] de novo dyspareunia;
    [cir] Vaginal scarring, shrinkage, and tightening;
    [cir] de novo vaginal bleeding;
    [cir] Atypical vaginal discharge;
    [cir] Fistula formation;
    [cir] de novo voiding dysfunction (e.g., incontinence);
    [cir] Neuromuscular problems (including groin and leg pain);
    [cir] Revision/resurgery;
    [cir] Recurrent prolapse;
     Summary of clinical data; and
     Step-by-step instructions, with images, on proper 
placement of the mesh.

J. Patient Labeling

    FDA would also expect patient labeling to be provided for each 
device, and it should include, but not be limited to: (1) An 
explanation of POP, including anatomical issues, causes, and symptoms; 
a discussion regarding all available treatment options, including known 
risks and benefits of mesh placement based on the results of the 
clinical trial conducted; (2) a statement that surgical mesh is a 
permanent implant; instructions for postoperative care; and (3) a 
notice of availability of an FDA Safety Communication. Patient labeling 
should also include a patient identification card that contains at a 
minimum the following information: Device name and lot number; patient 
name; date of implant; the type of repair performed (e.g., anterior or 
posterior); and the name and contact information for implanting 
physician and the device manufacturer.

VII. Opportunity To Request a Change in Classification

    Before requiring the filing of a PMA for a device, FDA is required 
by section 515(b)(2)(D) of the FD&C Act to provide an opportunity for 
interested persons to request a change in the classification of the 
device based on new information relevant to the classification. Any 
proceeding to reclassify the device will be under the authority of 
section 513(e) of the FD&C Act.
    A request for a change in the classification of surgical mesh for 
transvaginal POP repair devices is to be in the form of a 
reclassification petition containing the information required by Sec.  
860.123, including new information relevant to the classification of 
the device. Interested persons may also submit a reclassification 
petition related to the classification of the device to docket number 
for the proposed order reclassifying surgical mesh for transvaginal POP 
repair that is published elsewhere in this issue of the Federal 
Register.

VIII. 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.

IX. Paperwork Reduction Act of 1995

    This proposed 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 part 822 have been approved under OMB 
control number 0910-0449; and the collections of information under 21 
CFR part 801 have been approved under OMB control number 0910-0485.

X. Proposed Effective Date

    FDA is proposing that any final order based on this proposal become 
effective on the date of its publication in the Federal Register or at 
a later date if stated in the final order.

[[Page 24648]]

XI. 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 approval of an 
application for premarket 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 
approval of an application for premarket 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 
an application for premarket approval, resulting from changes issued in 
a final order, in the Code of Federal Regulations (CFR). Therefore, 
under section 515(b)(1)(A) of the FD&C Act, as amended by FDASIA, in 
this proposed order, we are proposing to require approval of an 
application for premarket approval for surgical mesh for transvaginal 
POP repair and, if this proposed order is finalized, we will make the 
language in Sec.  884.5980 consistent with the final version of this 
proposed order.

XII. Comments

    Interested persons may submit either electronic comments regarding 
this document to http://www.regulations.gov or written comments to the 
Division of Dockets Management (see ADDRESSES). It is only necessary to 
send one set of comments. Identify comments with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the Division of Dockets Management between 9 a.m. and 4 
p.m., Monday through Friday, and will be posted to the docket at http://www.regulations.gov.

XIII. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday, 
and are available electronically at http://www.regulations.gov. (FDA 
has verified all the Web site addresses in this reference section, but 
we are not responsible for any subsequent changes to the Web sites 
after this document publishes in the Federal Register.)

1. ``FDA Public Health Notification: Serious Complications 
Associated With Transvaginal Placement of Surgical Mesh in Repair of 
Pelvic Organ Prolapse and Stress Urinary Incontinence'', October 20, 
2008, available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/PublicHealthNotifications/ucm061976.htm.
2. ``FDA Safety Communication: UPDATE on Serious Complications 
Associated With Transvaginal Placement of Surgical Mesh for Pelvic 
Organ Prolapse,'' July 13, 2011, available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm262435.htm.
3. ``FDA Executive Summary: Surgical Mesh for Treatment of Women 
With Pelvic Organ Prolapse and Stress Urinary Incontinence, 
Obstetrics & Gynecological Devices Advisory Committee Meeting'', 
September 8-9, 2011, available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ObstetricsandGynecologyDevices/ucm262488.htm.
4. 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.
5. Blue Book Memo G-95-1 ``Use of International Standard 
ISO-10993, Biological Evaluation of Medical Devices Part 1: 
Evaluation and Testing,'' May 1, 1995, available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080735.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, it is 
proposed that 21 CFR part 884 be 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, Subpart F, 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 [90 DAYS AFTER DATE OF PUBLICATION OF FINAL ORDER FOR 
PREMARKET APPLICATION OR 30 MONTHS AFTER DATE OF PUBLICATION OF FINAL 
ORDER RECLASSIFYING INTO CLASS III, WHICHEVER IS LATER], 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 
[90 DAYS AFTER DATE OF PUBLICATION OF FINAL ORDER FOR PREMARKET 
APPROVAL APPLICATIONS OR 30 MONTHS AFTER DATE OF PUBLICATION OF FINAL 
ORDER RECLASSIFYING INTO CLASS III, WHICHEVER IS LATER] 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 intended for transvaginal 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: April 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-09909 Filed 4-29-14; 8:45 am]
BILLING CODE 4160-01-P