[Federal Register Volume 81, Number 2 (Tuesday, January 5, 2016)]
[Rules and Regulations]
[Pages 364-370]
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,
[email protected].
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
[[Page 365]]
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
[[Page 366]]
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