[Federal Register Volume 79, Number 84 (Thursday, May 1, 2014)]
[Proposed Rules]
[Pages 24634-24642]
[FR Doc No: 2014-09907]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 884

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

Reclassification of Surgical Mesh for Transvaginal Pelvic Organ
Prolapse Repair and Surgical Instrumentation for Urogynecologic
Surgical Mesh Procedures; Designation of Special Controls for
Urogynecologic Surgical Mesh Instrumentation

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

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SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing to reclassify surgical mesh for transvaginal pelvic organ
prolapse (POP) repair from class II to class III. FDA is proposing this
reclassification based on the tentative determination that general
controls and special controls together are not sufficient to provide
reasonable assurance of safety and effectiveness for this device. In
addition, FDA is proposing to reclassify urogynecologic surgical mesh
instrumentation from class I to class II. The Agency is also proposing
to establish special controls for surgical instrumentation for use with
urogynecologic surgical mesh. FDA is proposing this action, based on
the tentative determination that general controls by themselves are
insufficient to provide reasonable assurance of the safety and
effectiveness of these devices, and there is sufficient information to
establish special controls to provide such assurance. The Agency is
reclassifying both the surgical mesh for transvaginal repair and the
urogynecologic surgical mesh instrumentation on its own initiative
based on new information.

DATES: Submit either electronic or written comments on this proposed
order by July 30, 2014. Please see section XIII for the proposed
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-0297, 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-0297 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,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
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) establishes 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 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.
    Section 513(a)(1) of the FD&C Act defines three classes of devices.
Class I devices are those devices for which the general controls of the
FD&C Act (controls authorized by or under sections 501, 502, 510, 516,
518, 519, or 520 of the FD&C Act (21 U.S.C. 351, 352, 360, 360f, 360h,
360i, and 360j), or any combination of such sections) are sufficient to
provide reasonable assurance of safety and effectiveness; or those
devices for which insufficient information exists to determine that
general controls are sufficient to provide reasonable assurance of
safety and effectiveness or to establish special controls to provide
such assurance, but because the devices are not purported or
represented to be for a use in supporting or sustaining human life or
for a use that is of substantial importance in preventing impairment of
human health, and do not present a potential unreasonable risk of
illness or injury, are to be regulated by general controls (section
513(a)(1)(A) of the FD&C Act). Class II devices are those devices for
which the general controls by themselves are insufficient to provide
reasonable assurance of safety and effectiveness, but for which there
is sufficient information to establish special controls to provide such
assurance, including the issuance of performance standards, postmarket
surveillance, patient registries, development and dissemination of
guidelines, recommendations, and other appropriate actions the Agency
deems necessary to provide such assurance (section 513(a)(1)(B) of the
FD&C Act; see also Sec.  860.3(c)(2) (21 CFR 860.3(c)(2))). Class III
devices are those devices for which insufficient information exists to
determine that general controls and special controls would provide
reasonable assurance of safety and effectiveness, and are purported or
represented for a use in supporting or sustaining human life or for a
use that is of substantial importance in preventing impairment of human
health, or present a potential unreasonable risk of illness or injury
(section 513(a)(1)(C) of the FD&C Act).
    Section 513(e)(1) of the FD&C Act provides that FDA may, by
administrative order, reclassify a device based upon ``new
information.'' FDA can initiate a reclassification under section 513(e)
or an interested person may petition FDA to reclassify a device. The
term ``new information,'' as used in section 513(e) of the FD&C Act,
includes information developed as a result of a reevaluation of the
data before the Agency when the device was originally classified, as
well as information not presented, not available, or not developed at
that time. (See, e.g., Holland Rantos v. United States Department of
Health, Education, and Welfare, 587 F.2d 1173, 1174 n.1 (D.C. Cir.
1978); Upjohn v. Finch, 422 F.2d 944 (6th Cir. 1970); Bell v. Goddard,
366 F.2d 177 (7th Cir. 1966).)
    Reevaluation of the data previously before the Agency is an
appropriate basis for subsequent regulatory action where the
reevaluation is made in light of newly available regulatory authority
(see Bell v. Goddard, supra, 366 F.2d at 181; Ethicon, Inc. v. FDA, 762
F. Supp. 382, 389-91 (D.D.C. 1991)), or in light of changes in
``medical science'' (See Upjohn v. Finch, supra, 422 F.2d at 951.).
Whether data before the Agency are past or new data, the ``new
information'' to support reclassification under section 513(e) must be
``valid scientific evidence,'' as defined in Sec.  860.7(c)(2). (See,
e.g., General Medical Co. v. FDA, 770 F.2d 214 (D.C. Cir. 1985);
Contact Lens Mfrs. Assoc. v. FDA, 766 F.2d 592 (D.C. Cir. 1985), cert.
denied, 474 U.S. 1062 (1986).) To be considered in the reclassification
process, the ``valid scientific evidence'' upon which the Agency relies
must be publicly available. Publicly available information excludes
trade secret and/or confidential commercial information, e.g., the
contents of a pending premarket approval application (PMA) (see section
520(c) of the FD&C Act).
    Section 513(e)(1) of the FD&C Act sets forth the process for
issuing a final reclassification order. Specifically, prior to the
issuance of a final order reclassifying a device, the following must
occur: (1) Publication of a proposed order in the Federal Register; (2)
a meeting of a device classification

panel described in section 513(b) of the FD&C Act; and (3)
consideration of comments to a public docket. FDA has 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 and,
therefore, has met this requirement under section 513(e)(1) of the FD&C
Act. As explained further in section VIII, a meeting of a device
classification panel described in section 513(b) of the FD&C Act took
place in 2011 to discuss whether surgical mesh for transvaginal POP
repair should be reclassified to class III or remain in class II, and
the panel recommended that the device be reclassified into class III
because general controls and special controls would not be sufficient
to provide a reasonable assurance of safety and effectiveness. FDA is
not aware of new information since the 2011 panel that would provide a
basis for a different recommendation or findings. The 2011 panel
meeting did not include a specific discussion of surgical
instrumentation for use with urogynecologic surgical mesh and hence FDA
will convene a panel to discuss this issue prior to finalizing
reclassification of instrumentation for this use.
    Section 513(e)(1)(A)(i) of the FD&C Act requires that the proposed
reclassification order set forth the proposed reclassification and a
substantive summary of the valid scientific evidence concerning the
proposed reclassification, including the public health benefits of the
use of the device; the nature and if known, incidence of the risk of
the device; and in the case of reclassification from class II to class
III, why general controls and special controls together are not
sufficient to provide reasonable assurance of safety and effectiveness
for the device.
    In accordance with section 513(e)(1), the Agency is proposing,
based on new information that has come to the Agency's attention since
the original classification of surgical mesh, to reclassify surgical
mesh for transvaginal POP repair, based on the tentative determination
that general controls and special controls are not sufficient to
provide a reasonable assurance of safety and effectiveness. Also, the
Agency is proposing, based on new information, to reclassify
urogynecologic surgical mesh instrumentation from class I to class II,
and as part of the proposed reclassification and consistent with
section 513(a)(1)(B), is proposing to establish special controls for
urogynecologic surgical mesh instrumentation. FDA tentatively
determines that the general controls by themselves are insufficient to
provide reasonable assurance of safety and effectiveness of this
instrumentation, and there is sufficient information to establish
special controls to provide such assurance. FDA is proposing
reclassification of both devices based on its review of information
received through multiple sources. These sources include: (1)
Postmarket surveillance of medical device reports (MDRs), (2) concerns
raised by the clinical community and citizens, and (3) the published
literature.
    Section 515(b) of the FD&C Act (21 U.S.C. 360e) provides that for
any class III preamendments device, FDA shall by order require such
device to have approval of a PMA or notice of completion of a product
development protocol (PDP). Elsewhere in this issue of the Federal
Register, FDA is proposing to require the filing of a PMA or notice of
completion of a PDP, which will only be finalized if FDA reclassifies
surgical mesh for transvaginal POP repair to class III.

II. Regulatory History of the Devices

    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 POP repair under the general surgical mesh classification
regulation, Sec.  878.3300. FDA has cleared over 100 510(k) submissions
for surgical meshes with a POP indication. Urogynecologic surgical mesh
instrumentation is currently classified as a class I device under Sec.
876.4730 (21 CFR 876.4730) (manual gastroenterology-urology surgical
instrument and accessories) or Sec.  878.4800 (manual surgical
instrument for general use).

III. Device Description

    Surgical mesh 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).
    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.
    Many mesh products include instrumentation specifically designed to
aid in insertion, placement, fixation, and anchoring of the mesh in the
body. Instrumentation can also be provided separately from the mesh
implant. This instrumentation is typically composed of a stainless-
steel needle attached to a plastic handle and is similar to trocar
needles used in general surgery. The needles used in mesh-augmented
urogynecologic repair are designed to aid transvaginal or
transabdominal insertion and placement of the mesh. Instrumentation for
mesh-augmented POP repair can also be designed for a specific
anatomical compartment.

IV. Proposed Reclassification

    FDA is proposing that surgical mesh for transvaginal POP repair be
reclassified from class II to class III. FDA is also proposing that
urogynecologic surgical mesh instrumentation be reclassified from class
I to class II with special controls. In accordance with sections
513(e)(1) of the FD&C Act, FDA, on its own initiative, is proposing to
reclassify these devices based on new information.

V. Dates New Requirements Apply

    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. If FDA finalizes this order,
surgical mesh for transvaginal POP repair will be reclassified into
class III and urogynecologic surgical mesh instrumentation will be
reclassified into class II with special controls.

VI. Public Health Benefits and Risks to Health

    As required by section 513(e)(1)(A)(I) of the FD&C Act, FDA is
providing a substantive summary of the valid scientific evidence
regarding the public health benefit of the use of surgical mesh for
transvaginal POP repair and urogynecologic surgical mesh
instrumentation, and the nature and, if known, incidence of the risk of
the devices.
    The devices have the potential to benefit the public health by
aiding in the correction of cystocele (anterior repair), rectocele
(posterior repair), uterine prolapse, and vaginal apical prolapse
(apical repair).

    FDA has evaluated the risks to health associated with the use of
surgical mesh indicated for transvaginal POP repair and has identified
the following risks for this device:
    1. Perioperative risks. Organ perforation or injury and bleeding
(including hemorrhage/hematoma).
    2. Vaginal mesh exposure (mesh visualized through the vaginal
epithelium, e.g., separated incision line) (Ref. 1). 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 (passage of mesh into visceral organ, including
the bladder or rectum) (Ref. 1). 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
include 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).
    FDA has also evaluated the risks to health associated with the use
of urogynecologic surgical mesh instrumentation and has identified the
following risks for this device:
    1. Perioperative risks. Organ perforation or injury and bleeding
(including hemorrhage/hematoma).
    2. Damage to blood vessels, nerves, connective tissue, and other
structures. This may be caused by improperly designed and/or misused
surgical mesh instrumentation. Clinical sequelae include pelvic pain
and neuromuscular problems.
    3. Adverse tissue reaction. This may be caused by non-biocompatible
materials.
    4. Infection. This may be due to inadequate sterilization and/or
reprocessing instructions or procedures.
    As discussed further in this document, these findings regarding the
public health benefits and risks to health associated with surgical
mesh for transvaginal POP repair and urogynecologic surgical mesh
instrumentation are based on publicly available information, including
the published literature and MDRs, and are supported by the reports and
recommendations of the Obstetrics and Gynecological Devices Panel (the
Panel) from the meeting on September 8 and 9, 2011.

VII. Summary of the Data Upon Which the Reclassification Is Based

A. Safety of Surgical Mesh Used for Transvaginal Repair of Pelvic Organ
Prolapse

    In the published literature, mesh exposure (also referred to as
erosion or extrusion in the published literature) is the most common
and consistently reported mesh-related complication following
transvaginal POP repair with mesh. In this document, we use the term
``mesh exposure'' to refer to mesh visualized through the vaginal
epithelium, and we use the term ``mesh extrusion'' to refer to passage
of mesh into a visceral organ, including into the bladder or rectum.
    Mesh exposure can result in serious complications unique to mesh
procedures and is not experienced by patients who undergo traditional
repair. Mesh exposure may require mesh removal or excision to manage
the sequelae (e.g., pelvic pain, infection (including pelvic abscess),
and dyspareunia). This complication can be life altering for some women
as mesh removal or excision may require multiple surgeries and sequelae
may persist despite mesh removal (Ref. 2). Other clinical sequelae
associated with mesh exposure include vaginal bleeding and vaginal
discharge (Refs. 2 and 3).
    Less common is mesh extrusion partly or through the bladder or
rectal mucosa (Ref. 4). In addition to the clinical sequelae previously
described, the former may require a suprapubic catheter (Ref. 4), and
when the latter occurs ``a diverting colostomy may be needed to excise
and repair the erosion site and lead[s] to life-long morbidity for the
patient'' (Ref. 5).
    A 2011 systematic review of the safety of transvaginal POP repair
with mesh by Abed et al. cited a summary incidence of mesh exposure of
10.3 percent (95 percent CI, 9.7-10.9 percent; range 0-29.7 percent
within 12 months of surgery from 110 studies including 11,785 women in
whom mesh was used for transvaginal POP repair) (Ref. 3). The incidence
of mesh exposure did not differ between nonabsorbable synthetic mesh
(10.3 percent) and biologic graft material (10.1 percent) (Ref. 3).
    For non-absorbable synthetic mesh exposures, 56 percent (448/795)
of patients required surgical excision in the operating room with some
women requiring two to three additional surgeries (Ref. 3). The one
randomized controlled trial (RCT) with available long-term outcomes of
anterior repair with nonabsorbable synthetic mesh found that 5 percent
of patients had unresolved mesh exposure at 3 years of followup (Ref.
6).
    Less information is available about management of exposure from
biologic grafts. The review by Abed et al. found that, for the 35 women
in which management of exposure from biologic grafts was discussed,
half responded to local treatment with topical agents. For the
remainder, management of the exposure was not discussed (Ref. 3).
    Mesh/tissue contraction, causing vaginal scarring, shrinkage,
tightening, and/or pain in association with transvaginal POP repair
with mesh, is another mesh-specific adverse event that has been
reported in the literature (Refs. 7 and 8). However, vaginal scarring,
shrinkage, and tightening can also occur following traditional repair.
    Other postoperative adverse events commonly reported in the
literature that are associated with POP repair with mesh are pelvic
pain, infection, de novo dyspareunia, de novo voiding dysfunction
(e.g., incontinence), neuromuscular problems (including groin and leg
pain), and additional corrective surgeries for complications or
recurrent prolapse (Refs. 2, 7, 9, 10).
    These adverse events are not unique to POP procedures with mesh,
but repeat surgery for complications appears to be highest for
transvaginal POP repair with mesh, followed by sacrocolpopexy and
traditional repair (Refs. 11 and 12). A systematic review of re-surgery
rates following POP repair found that transvaginal surgery with mesh is
associated with a higher rate of complications requiring reoperation
compared to sacrocolpopexy (abdominal POP repair with mesh) or
traditional transvaginal repair (7.2 percent vs. 4.8 percent vs. 1.9
percent, respectively) (Ref. 11). (For transvaginal surgery with mesh,
24 studies including 3,425 women with mean followup of 17 months were
included in this systematic review. For sacrocolpopexy, 52 studies
including 5,639 women with mean followup of 26 months were included,
and for traditional transvaginal repair, 48 studies including 7,827
women with mean followup of 32 months were included.) From the one RCT
that directly compared sacrocolpopexy to transvaginal POP repair with
mesh (both using synthetic nonabsorbable mesh), overall re-surgery
within 2 years postoperative was significantly more common following
transvaginal POP repair with mesh than laparoscopic sacrocolpopexy,
with rates of 22 percent (12/55) and 5 percent (3/53), respectively
(p=0.006) (Ref. 12). De novo

stress urinary incontinence has been reported to occur more frequently
following anterior repair with mesh compared to traditional anterior
repair (Ref. 13). Currently, there is no evidence in the literature
that other postoperative adverse events occur more commonly following
mesh repairs compared to non-mesh repairs.
    The findings within the literature are consistent with the types
and relative frequency of adverse events that have been reported to FDA
through the Manufacturer and User Facility Device Experience (MAUDE)
database. Between January 1, 2011, and December 31, 2013, FDA received
19,043 adverse events for surgical mesh used for POP repair. The most
frequently reported adverse events were pain, erosion, and injury.
Further discussion of the risks associated with surgical mesh for
transvaginal POP repair is provided in FDA materials for the September
2011 panel meeting (Ref. 14).

B. Effectiveness of Surgical Mesh Used for Transvaginal Repair of
Pelvic Organ Prolapse

    The majority of trials evaluating effectiveness of POP repair use a
primary effectiveness outcome of ideal anatomic support, defined as
prolapse Stage 0 or 1 (i.e., the lowest point of prolapse is more than
1 cm proximal to the vaginal opening) on the Pelvic Organ Prolapse
Quantification (POP-Q) scale. This outcome measure was chosen as a
means to provide a quantitative description of the degree of prolapse,
but it is not correlated with POP symptoms or patient assessment of
improvement (Ref. 15). Additionally, assessment of prolapse stage
suffers from interobserver variability (Ref. 16).
    The published literature reveals that, although transvaginal POP
repair with mesh often restores anatomy, it has not been shown to
improve clinical benefit over traditional non-mesh repair and, given
the risks associated with mesh, the probable benefits from use of the
device do not outweigh the probable risks. This is particularly true
for apical and posterior repair with mesh (Refs. 9, 10, 17-22).
    A systematic review of transvaginal mesh kits for apical repair
found that they appear effective in restoring apical prolapse in the
short term, but long-term outcomes are unknown (Ref. 23). Additionally,
there is no evidence that transvaginal apical repair with mesh is more
effective than traditional transvaginal apical repair. Specifically,
only two RCTs have evaluated apical repair with mesh compared to
traditional transvaginal repair, and neither found a significant
improvement in anatomic outcome with mesh augmentation (Refs. 17 and
18). Both of these RCTs evaluated synthetic nonabsorbable transvaginal
mesh kits for multicompartment repair (i.e., anterior, posterior, or
total (anterior and posterior) mesh placement). Of these two trials,
Withagen et al. reported an anatomic benefit in the posterior
compartment following posterior repair with mesh, but subjects in the
trial who underwent posterior repair with mesh had less posterior
prolapse at baseline than subjects who underwent traditional repair
(Ref. 18). Therefore, the mesh arm of the Withagen et al. study was
less ``challenged'' than the non-mesh arm. Iglesia et al. did not show
an anatomic benefit in the posterior compartment following posterior
repair with mesh augmentation (Ref. 17).
    The only RCT to compare posterior repair with mesh to traditional
posterior repair (without multiple compartment repair) showed that
subjects who underwent repair using a synthetic absorbable mesh had
worse anatomic outcomes than those who underwent traditional repair
(Ref. 19). Two other RCTs that compared combined anterior and posterior
repair with mesh to traditional anterior and posterior repair found no
additional anatomic benefit to mesh augmentation in the posterior
compartment (Refs. 19 and 20). One of these used a synthetic absorbable
mesh (Ref. 19) and the other used a synthetic nonabsorbable mesh (Ref.
20).
    A 2010 review of management of posterior vaginal wall repair by
Kudish and Iglesia states ``studies published to date do not support
use of biologic or synthetic absorbable grafts in reconstructive
surgical procedures of the posterior compartment as these repairs have
not improved anatomic or functional outcomes over traditional posterior
[repair]'' (Ref. 5). At the time of publication of this review, no
studies comparing posterior repair with synthetic non-absorbable mesh
to traditional posterior repair had been performed. However, as noted
previously, reported outcomes in the three trials in which synthetic
non-absorbable mesh was used in the posterior compartment (Refs. 17,
18, 20) were generally consistent with the conclusions of Kudish and
Iglesia (Ref. 5). These authors also note that, when erosion of vaginal
mesh occurs in the posterior compartment, it often requires excision of
exposed mesh.
    The literature does suggest that there may be an anatomic benefit
to anterior repair with mesh augmentation (Refs. 6, 9, 10, 13, 18, 19,
22, 24-30); however, there are significant limitations in the available
data. The majority of the trials that showed an anatomic benefit to
anterior repair with mesh augmentation compared to traditional repair
used synthetic non-absorbable mesh, but only one used a synthetic
absorbable material (Ref. 19) and one used a non-synthetic material
(Ref. 28). Therefore, these results may not be generalizable to all
mesh types. Only 2 of 11 peer-reviewed publications on anterior
prolapse repair were evaluator-blinded prospective RCTs (Refs. 20, 27)
such that evaluator bias was minimized, and these two RCTs reached
different conclusions. One showed no anatomical improvement for the
mesh cohort compared to the traditional non-mesh repair cohort (Ref.
20). The second evaluator-blinded RCT did show an anatomic benefit for
mesh in the anterior compartment, but this RCT was a single-center,
single-investigator study (Ref. 27). Therefore, the outcomes from this
study may not be representative of procedures performed at other
centers by other operators.
    Although multiple trials reported in the literature report a
benefit to POP repair with mesh compared to traditional repair, these
trials were designed to evaluate an endpoint indicative of ideal
anatomic support, rather than an outcome more representative of
improvement in patient symptoms. A re-analysis of one RCT comparing
three techniques for anterior repair (two without mesh and one with
synthetic absorbable mesh augmentation) showed no differences in
effectiveness across all study groups when less stringent (and
arguably, more clinically meaningful) criterion for success, defined as
prolapse at or above the vaginal opening, was applied (Ref. 31). The
original trial defined recurrent prolapse as greater than Stage 1 at 1
year postimplant and, using this definition, had concluded that
subjects who had anterior repair with mesh augmentation were less
likely to have recurrent prolapse.
    Additionally, patients who undergo traditional repair have
equivalent improvement in quality of life (Refs. 20, 22, 27, 32)
compared to patients who undergo transvaginal POP repair with mesh. The
differential in reported success rates between mesh and non-mesh
repairs is not reflected in the comparison of quality of life outcomes
where no difference was observed, indicating that use of a non-symptom
related outcome measure (i.e., ideal pelvic support determined by POP-
Q) likely accounts for this differential.

C. Safety and Effectiveness of Surgical Instrumentation for Use With
Surgical Mesh for Transvaginal Pelvic Organ Prolapse Repair and Other
Urogynecologic Procedures

    Implantation of surgical mesh for urogynecologic procedures, such
as POP repair, is a complex procedure, and specialized surgical
instrumentation has been developed to aid the insertion, placement,
fixation, and anchoring of the surgical mesh. The procedure is
performed ``blind,'' such that the surgeon cannot directly visualize
placement of the surgical mesh, and is reliant on the surgical
instrumentation, palpation of anatomic landmarks, and experience for
accessing critical ligaments and attaching anchors and other devices
needed to secure the mesh. Because adverse events related to surgical
mesh are typically submitted with reference to the product code for the
mesh itself, it is difficult to distinguish adverse events related to
the surgical instrumentation from those directly related to the
surgical mesh. However, as was discussed by the Panel (see section
VIII), there is a concern that the use of surgical instrumentation,
such as long trocars, can result in significant adverse events to
patients. From January 1, 2011, to December 31, 2013, FDA received 843
reports related to bleeding, hematoma, and blood loss, 42 reports
related to organ perforation, and 196 reports of neuromuscular problems
through the MAUDE database for surgical mesh indicated for POP. In
addition, clinical studies, case reports, and systematic literature
reviews in the published literature have reported similar perioperative
adverse events (Refs. 7, 9, 11-13, 17, 18, 22, 24-25, 29). Given the
nature of these adverse events, it is reasonable to assume that they
were caused by or related to the use of instrumentation to insert,
place, fix, or anchor the surgical mesh perioperatively.
    In addition, use of surgical instrumentation may lead to adverse
tissue reaction as a result of using non-biocompatible materials. It
may also lead to infection due to inadequate sterilization, inadequate
reprocessing procedures, or use beyond the labeled expiration date.
These are general risks that apply to devices that have patient
contact, are provided sterile, and are reusable.
    FDA tentatively concludes that appropriately designed and labeled
instrumentation is critical to the safe and effective use of surgical
mesh for female urological and gynecological procedures, and that
surgical instrumentation for this use must be adequately tested prior
to marketing.

VIII. 2011 Classification Panel Meeting

    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. 33). 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 titled ``UPDATE on Serious Complications Associated With
Transvaginal Placement of Surgical Mesh for Pelvic Organ Prolapse''
(Ref. 34). On the same date, FDA also issued a white paper titled
``Urogynecologic Surgical Mesh: Update on the Safety and Effectiveness
of Transvaginal Placement for Pelvic Organ Prolapse'' (Ref. 35). The
continued reports of adverse events also prompted FDA to consider the
information available regarding the use of surgical mesh for
transvaginal POP repair and to evaluate whether the classification of
this device type should be reconsidered.
    In accordance with section 513(e)(1) of the FD&C Act and 21 CFR
part 860, subpart C, on September 8 and 9, 2011, FDA referred the
proposed reclassification to the Panel for its recommendations on the
proposed change in the device's classification from class II to class
III, among other related questions (Ref. 14). 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 for this use than traditional non-mesh
surgery, especially for the apical and posterior vaginal compartments.
    The Panel consensus was that premarket clinical data are needed for
surgical mesh for transvaginal POP repair. The majority of panel
members recommended that these devices be evaluated against a control
arm of traditional ``native-tissue'' (nonmesh) repair to demonstrate a
reasonable assurance of safety and effectiveness for the devices. Panel
members also 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 should
undergo a comparison to native tissue repair in order to establish a
reasonable assurance of safety and effectiveness. The Panel's 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. Panel members also expressed concern that the use of surgical
instrumentation, such as long trocars, can result in significant
adverse events to patients.
    Panel members also concluded that manufacturers of surgical mesh
indicated for transvaginal POP repair should conduct postmarket studies
of currently marketed devices. Beginning on January 3, 2012, FDA issued
postmarket surveillance study orders to manufacturers under section 522
of the FD&C Act (21 U.S.C. 360l) (``section 522 orders'') for
transvaginal POP mesh products that are already legally marketed. As of
the date of this order, FDA had issued 126 section 522 orders to 33
manufacturers of transvaginal POP mesh products.
    The Panel also emphasized that additional work should be focused on
patient labeling and informed consent, including providing benefit-risk
information on available treatment options for POP--surgical and
nonsurgical 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, and to use
existing databases and new data collection tools (e.g., registries) to
develop a meaningful database on postmarket clinical outcomes.

IX. Summary of Reasons for Reclassification

    Based on the information reviewed by FDA relating to the safety and
effectiveness of surgical mesh for transvaginal POP repair, including
the valid scientific evidence discussed in section VII, FDA tentatively
concludes that surgical mesh for transvaginal POP repair should be
reclassified from class II to class III. As established in section

513(a)(1)(C) of the FD&C Act and Sec.  860.3(c)(3), a device is in
class III if insufficient information exists to determine that general
controls and special controls together are sufficient to provide
reasonable assurance of its safety and effectiveness and the device is
purported or represented to be for a use that is life-supporting or
life-sustaining, or for a use which is of substantial importance in
preventing impairment of human health, or if the device presents a
potential unreasonable risk of illness or injury. FDA tentatively
agrees with the Panel consensus that the safety and effectiveness of
this device type has not been established and that 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. Therefore, FDA tentatively concludes that general
and special controls together are not sufficient to provide a
reasonable assurance of the safety and effectiveness of surgical mesh
intended for transvaginal POP repair. In addition, in the absence of an
established positive benefit-risk profile, the risks to health
associated with the use of surgical mesh for transvaginal POP repair
identified previously present a potential unreasonable risk of illness
or injury.
    Based on FDA's tentative determination that general controls and
special controls together are not sufficient to provide reasonable
assurance of safety and effectiveness of surgical mesh intended for
transvaginal POP repair and that the device presents a potential
unreasonable risk of illness or injury, FDA proposes to reclassify
surgical mesh for transvaginal POP repair from class II to class III.
    The procedure for implanting surgical mesh typically involves use
of surgical instrumentation, some of which is specifically designed and
labeled for urogynecologic procedures, including transvaginal POP
procedures. Instrumentation for this use is currently classified under
existing regulations for class I devices, including Sec.  876.4730
(manual gastroenterology-urology surgical instrument and accessories)
or Sec.  878.4800 (manual surgical instrument for general use).
    FDA tentatively concludes that valid scientific evidence
demonstrates that special controls, in addition to the general
controls, are necessary to provide a reasonable assurance of safety and
effectiveness for surgical instrumentation used for implanting surgical
mesh for urogynecological use.
    Therefore, FDA proposes to reclassify instrumentation used for
implanting surgical mesh for urogynecological use from class I to class
II (special controls). If the proposed reclassification is finalized, a
premarket notification submission that addresses, among other things,
the special controls established for the device, would be required
prior to marketing the device.

X. Special Controls

    FDA tentatively concludes that the following special controls, in
addition to general controls, are sufficient to mitigate the risks to
health described in section VI attributable to the surgical
instrumentation for implanting surgical mesh for urogynecological
procedures:
     The device must be demonstrated to be biocompatible;
     The device must be demonstrated to be sterile;
     Performance data must support the shelf life of the device
by demonstrating package integrity and device functionality over the
requested shelf life;
     Bench and/or cadaver testing must demonstrate safety and
effectiveness in expected-use conditions; and
     Labeling must include:
    [cir] Information regarding the mesh design that may be used with
the device;
    [cir] Detailed summary of the clinical evaluations pertinent to use
of the device;
    [cir] Expiration date; and
    [cir] Where components are intended to be sterilized by the user
prior to initial use and/or are reusable, validated methods and
instructions for sterilization and/or reprocessing of any reusable
components.
    Table 1 shows how the risks to health identified in section VI
associated with urogynecological surgical mesh instrumentation can be
mitigated by the proposed special controls.

    Table 1--Health Risk and Mitigation Measure for Urogynecological
                      Surgical Mesh Instrumentation
------------------------------------------------------------------------
              Identified risk                     Special controls
------------------------------------------------------------------------
Perioperative Injury......................  Bench and/or Cadaver
                                             Testing.
                                            Labeling.
                                            Shelf Life Testing.
Pelvic Pain and Neuromuscular Problems....  Bench and/or Cadaver
                                             Testing.
                                            Shelf Life Testing.
                                            Labeling.
Infection.................................  Sterilization Validation.
                                            Shelf Life Testing.
                                            Labeling
Adverse Tissue Reaction...................  Biocompatibility.
------------------------------------------------------------------------

    FDA believes that bench and/or cadaver testing can help ensure that
urogynecologic surgical mesh instrumentation is appropriately designed
and limits damage to blood vessels, nerves, connective tissue, and
other structures. Also, such evaluation may help limit the adverse
events, such as perioperative injury (organ perforation or injury and
bleeding), pelvic pain, and neuromuscular problems, reported to the
MAUDE database and described in the published literature as discussed
in section VII. In addition, labeling specifying the mesh type that may
be used with the device and provision of a detailed summary of the
clinical evaluations pertinent to use of the device will also mitigate
these risks. Lastly, shelf life testing demonstrating that the device
maintains its functionality over the duration of its shelf life will
also mitigate damage to blood vessels, nerves, connective tissue, and
other structures, and perioperative risks.
    Also, the risk of adverse tissue reaction as a result of using non-
biocompatible materials can be mitigated by biocompatibility testing.
FDA finds that the risk of infection due to inadequate sterilization
and/or reprocessing instructions/procedures can be mitigated through
sterilization validation testing and the inclusion of validated
reprocessing instructions in the device labeling. In addition, FDA
believes that shelf life testing and inclusion of an expiration date on
the labeling will mitigate the risk of infection by ensuring that the
device maintains its sterility over the duration of its shelf life. The
expiration date may prevent use of the device after its validated shelf
life.
    FDA clarifies here that these special controls are specific to
surgical instrumentation specifically intended to be used with surgical
mesh for urogynecological procedures. FDA intends to evaluate
instrumentation provided with a mesh kit as part of the review of that
surgical mesh.
    In addition, the surgical instrumentation used for implanting
surgical mesh for urogynecological procedures are prescription devices
within the meaning of 21 CFR 801.109.

XI. Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this proposed
reclassification 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.

XII. 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 21 CFR 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.

XIII. 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.

XIV. Codification of Orders

    Prior to the amendments by FDASIA, section 513(e) of the FD&C Act
provided for FDA to issue regulations to reclassify devices. Section
513(e) as amended requires FDA to issue a final order rather than a
regulation. FDA will codify reclassifications resulting from changes
issued in final orders in the Code of Federal Regulations (CFR).
Changes resulting from final orders will appear in the CFR as changes
to codified classification determinations or as newly codified orders.
Therefore, under section 513(e)(1)(A)(i) of the FD&C Act, as amended by
FDASIA, in this proposed order we are proposing to codify the
reclassification of surgical mesh for transvaginal pelvic organ
prolapse repair into class III and proposing to codify the
reclassification of specialized surgical instrumentation for use with
urogynecologic surgical mesh devices into class II (special controls).

XV. Comments

    Interested persons may submit either electronic comments regarding
this proposed order 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.

XVI. References

    FDA has placed the following references on display in the Division
of Dockets Management (see ADDRESSES). Interested persons may see them
between 9 a.m. and 4 p.m., Monday through Friday, and online 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. Haylen, B.T., et al., ``An International Urogynecological
Association (IUGA)/International Continence Society (ICS) Joint
Terminology and Classification of the Complications Related Directly
to the Insertion of Prostheses (Meshes, Implants, Tapes) and Grafts
in Female Pelvic Floor Surgery,'' International Urogynecology
Journal, 22(3): pp. 3-15, 2011.
2. Margulies, R.U., et al., ``Complications Requiring Reoperation
Following Vaginal Mesh Kit Procedures for Prolapse,'' American
Journal of Obstetrics and Gynecology, 199: pp. 678.e1-678.e4, 2008.
3. Abed, H., et al., ``Incidence and Management of Graft Erosion,
Wound Granulation, and Dyspareunia Following Vaginal Prolapse Repair
With Graft Materials: A Systematic Review,'' International
Urogynecology Journal, 22(7): pp. 789-798, 2011.
4. Firoozi, F. and H. Goldman, ``Transvaginal Excision of Mesh
Erosion Involving the Bladder After Mesh Placement Using a Prolapse
Kit: A Novel Technique,'' Urology, 75(1): pp. 203-206, 2010.
5. Kudish, B.I. and C.B. Iglesia, ``Posterior Wall Prolapse and
Repair,'' Clinical Obstetrics and Gynecology, 53(1): pp. 59-71,
2010.
6. Nieminen, K., et al., ``Outcomes After Anterior Vaginal Wall
Repair With Mesh: A Randomized, Controlled Trial with a 3 Year
Follow-Up,'' American Journal of Obstetrics and Gynecology, 203(3):
p. 235.e1-235.e8, 2010.
7. Caquant, F., et al., ``Safety of Trans Vaginal Mesh Procedure:
Retrospective Study of 684 Patients,'' Journal of Obstetrics and
Gynecology Research, 34(4): pp. 449-456, 2008.
8. Feiner, B., et al., ``Vaginal Mesh Contraction: Definition,
Clinical Presentation, and Management,'' Obstetrics & Gynecology,
115(2 Pt. 1): pp. 325-330, 2010.
9. Maher, C.F., et al., ``Surgical Management of Pelvic Organ
Prolapse in Women,'' Cochrane Database of Systematic Review, 4:
CD004014, 2010.
10. Maher, C.F., et al., ``Surgical Management of Pelvic Organ
Prolapse in Women,'' Cochrane Database of Systematic Review, 4:
CD004014, 2013.
11. Diwadkar, G.B., et al., ``Complication and Reoperation Rates
After Apical Vaginal Prolapse Surgical Repair: A Systematic
Review,'' Obstetrics & Gynecology, 113(2 Pt. 1): pp. 67-73, 2009.
12. Maher, C.F., et al., ``Laparoscopic Sacral Colpopexy Versus
Total Vaginal Mesh for Vaginal Vault Prolapse: A Randomized Trial,''
American Journal of Obstetrics & Gynecology, 204(4): p. 360.e1-
360.e7, 2011.
13. Altman, D., et al., ``Anterior Colporrhaphy Versus Transvaginal
Mesh for Pelvic-Organ Prolapse,'' New England Journal of Medicine,
364: pp. 1826-1836, 2011.
14. FDA Meeting of the Obstetrics and Gynecological Devices Panel,
September 8 and 9, 2011, available at http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/ObstetricsandGynecologyDevices/ucm262488.htm.
15. Barber, M.D., et al., ``Defining Success After Surgery for
Pelvic Organ Prolapse,'' Obstetrics & Gynecology, 114(3): pp. 600-
609, 2009.
16. Whiteside J.L., et al., ``Clinical Evaluation of Anterior
Vaginal Wall Support Defects: Interexaminer and Intraexaminer
Reliability,'' American Journal Obstetrics and Gynecology, 191(1):
pp. 100-104, 2004.
17. Iglesia, C.B., et al., ``Vaginal Mesh for Prolapse: A Randomized
Controlled Trial,'' Obstetrics & Gynecology, 116(2 Pt. 1): pp. 293-
303, 2010.
18. Withagen, M.I., et al., ``Trocar-Guided Mesh Compared With
Conventional Vaginal Repair in Recurrent Prolapse: A Randomized
Controlled Trial,'' Obstetrics & Gynecology, 117(2 Pt. 1): pp. 242-
250, 2011.
19. Sand, P.K., et al., ``Prospective Randomized Trial of
Polyglactin 910 Mesh to Prevent Recurrence of Cystoceles and
Rectoceles,'' American Journal of Obstetrics and Gynecology, 184(7):
pp. 1357-1364, 2001.
20. Carey, M., et al., ``Vaginal Repair With Mesh Versus
Colporrhaphy for Prolapse: A Randomised Controlled Trial,'' British
Journal of Obstetrics and Gynecology, 116(10): pp. 1380-1386, 2009.
21. Paraiso, M.F.R., et al., ``Rectocele Repair: A Randomized Trial
of Three Surgical Techniques Including Graft Augmentation,''
American Journal of Obstetrics and Gynecology, 195(6): pp. 1762-
1771, 2006.
22. Sung, V.W., et al., Society of Gynecologic Surgeons Systematic
Review Group. ``Graft Use in Transvaginal Pelvic Organ Prolapse and
Urinary Incontinence,'' Obstetrics & Gynecology, 112(5): pp. 1131-
1142, 2008.
23. Feiner, B., et al., ``Efficacy and Safety of Transvaginal Mesh
Kits in the Treatment of Prolapse of the Vaginal Apex: A Systematic
Review,'' British Journal of Obstetrics and Gynecology, 116(1): pp.
15-24, 2009.

24. Hiltunen, R., et al., ``Low-Weight Polypropylene Mesh for
Anterior Vaginal Wall Prolapse: A Randomized Controlled Trial,''
Obstetrics & Gynecology, 110(2 Pt. 2): pp. 455-462, 2007.
25. Jia, X., et al., ``Efficacy and Safety of Using Mesh or Grafts
in Surgery for Anterior and/or Posterior Vaginal Wall Prolapse:
Systematic Review and Meta-Analysis,'' British Journal of Obstetrics
and Gynecology, 115: pp. 1350-1361, 2008.
26. Foon, R., et al., ``Adjuvant Materials in Anterior Vaginal Wall
Prolapse Surgery: A Systematic Review of Effectiveness and
Complications,'' International Urogyneacology Journal, 19: pp. 1697-
1706, 2008.
27. Nguyen, J.N. and R.J. Burchette, ``Outcome After Anterior
Vaginal Prolapse Repair: A Randomized Controlled Trial,'' Obstetrics
& Gynecology, 111(4): pp. 891-898, 2008.
28. Meschia, M., et al., ``Porcine Skin Collagen Implants to Prevent
Anterior Vaginal Wall Prolapse Recurrence: A Multicenter, Randomized
Study,'' Journal of Urology, 177(1): pp. 192-195, 2007.
29. Sivaslioglu, A.A., E. Unlubilgin, and I. Dolen, ``A Randomized
Comparison of Polypropylene Mesh Surgery With Site-Specific Surgery
in the Treatment of Cystocoele,'' International Urogynecology
Journal and Pelvic Floor Dysfunction, 19(4): pp. 467-471, 2008.
30. Lunardelli, J.L., et al., ``Polypropylene Mesh vs. Site-Specific
Repair in the Treatment of Anterior Vaginal Wall Prolapse:
Preliminary Results of a Randomized Clinical Trial,'' Journal of the
Brazilian College of Surgeons, 36(3): pp. 210-216, 2009.
31. Chmielewski, L., et al., ``Reanalysis of a Randomized Controlled
Trial of Three Techniques of Anterior Colporrhaphy Using Clinically
Relevant Definitions of Success,'' American Journal of Obstetrics
and Gynecology, 205: 69.e1-69.e8, 2011.
32. Jia, X., et al., ``Systematic Review of the Efficacy and Safety
of Using Mesh in Surgery for Uterine or Vaginal Vault Prolapse,''
International Urogynecology Journal, 21: pp. 1413-1431, 2010.
33. ``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.
34. ``FDA Safety Communication: UPDATE on Serious Complications
Associated With Transvaginal Placement of Surgical Mesh for Pelvic
Organ Prolapse,'' July 2011, available at http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm262435.htm.
35. FDA White Paper entitled ``Urogynecologic Surgical Mesh: Update
on the Safety and Effectiveness of Transvaginal Placement for Pelvic
Organ Prolapse,'' July 2011, available at http://www.fda.gov/downloads/medicaldevices/safety/alertsandnotices/ucm262760.pdf.

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 Sec.  884.4910 to Subpart E to read as follows:

Sec.  884.4910  Specialized surgical instrumentation for use with
urogynecologic surgical mesh.

    (a) Identification. Surgical instrumentation for use with surgical
mesh for urogynecological procedures is a prescription device used to
aid in insertion, placement, fixation, or anchoring of surgical mesh
for procedures including transvaginal pelvic organ prolapse repair,
sacrocolpopexy (transabdominal pelvic organ prolapse repair), and
treatment of female stress urinary incontinence. Examples of such
surgical instrumentation include needle passers and trocars, needle
guides, fixation tools, and tissue anchors. This device does not
include manual gastroenterology-urology surgical instrument and
accessories (Sec.  876.4730) nor manual surgical instrument for general
use (Sec.  878.4800).
    (b) Classification. Class II (special controls). The special
controls for this device are:
    (1) The device must be demonstrated to be biocompatible;
    (2) The device must be demonstrated to be sterile;
    (3) Performance data must support the shelf life of the device by
demonstrating package integrity and device functionality over the
requested shelf life;
    (4) Bench and/or cadaver testing must demonstrate safety and
effectiveness in expected-use conditions; and
    (5) Labeling must include:
    (i) Information regarding the mesh design that may be used with the
device;
    (ii) Detailed summary of the clinical evaluations pertinent to use
of the device;
    (iii) Expiration date; and
    (iv) Where components are intended to be sterilized by the user
prior to initial use and/or are reusable, validated methods and
instructions for sterilization and/or reprocessing of any reusable
components.

0
3. Add Sec.  884.5980 to Subpart F to read as follows:

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

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

    Dated: April 25, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-09907 Filed 4-29-14; 8:45 am]
BILLING CODE 4160-01-P


[Federal Register: January 24, 2011 (Volume 76, Number 15)]
[Notices]
[Page 4141]
[DOCID:fr24ja11-91]

=======================================================================
-----------------------------------------------------------------------

SECURITIES AND EXCHANGE COMMISSION

Sunshine Act Meeting

    Notice is hereby given, pursuant to the provisions of the
Government in the Sunshine Act, Public Law 94-409, that the Securities
and Exchange Commission will hold a Closed Meeting on Thursday, January
27, 2011 at 2 p.m.
    Commissioners, Counsel to the Commissioners, the Secretary to the
Commission, and recording secretaries will attend the Closed Meeting.
Certain staff members who have an interest in the matters also may be
present.
    The General Counsel of the Commission, or his designee, has
certified that, in his opinion, one or more of the exemptions set forth
in 5 U.S.C. 552b(c)(3), (5), (7), 9(B) and (10) and 17 CFR
200.402(a)(3), (5), (7), 9(ii) and (10), permit consideration of the
scheduled matters at the Closed Meeting.
    Commissioner Casey, as duty officer, voted to consider the items
listed for the Closed Meeting in a closed session.
    The subject matter of the Closed Meeting scheduled for Thursday,
January 27, 2011 will be:

    institution and settlement of injunctive actions; institution
and settlement of administrative proceedings; and other matters
relating to enforcement proceedings.

    At times, changes in Commission priorities require alterations in
the scheduling of meeting items.
    For further information and to ascertain what, if any, matters have
been added, deleted or postponed, please contact:
    The Office of the Secretary at<PHONE_NUMBER>.

    Dated: January 20, 2011.
Elizabeth M. Murphy,
Secretary.
[FR Doc. 2011-1513 Filed 1-20-11; 4:15 pm]
BILLING CODE 8011-01-P


                             Supporting Statement
                                      for
                        Information Collection Request

          EPA's Light-Duty In-Use Vehicle Testing Program (Renewal)

                                EPA ICR 0222.12

                           OMB Control No: 2060-0086

                                February, 2021

                             Compliance Division
                   Office of Transportation and Air Quality
                         Office of Air and Radiation
                     U.S. Environmental Protection Agency

Section 1: Identification of the Information Collection

1(a) Title and Number of the Information Collection

	EPA's Light-Duty In-Use Vehicle Testing Program (Renewal), EPA ICR Number 0222.12, OMB Control Number 2060-0086. This ICR was formerly titled "EPA's In-Use Vehicle and Engine Testing Programs." This ICR includes only the light-duty vehicle portion of the in-use testing program. The heavy-duty and off-road vehicle and engine programs are included under OMB Control Number 2060-0287.

1(b) Short Characterization/Abstract

	The Environmental Protection Agency (EPA), Office of Transportation and Air Quality, Compliance Division, conducts an integrated motor vehicle and engine emission compliance program. Motor vehicles and engines are first evaluated as prototypes prior to production; those designs that meet applicable criteria are licensed for introduction into commerce. EPA also has discretion to conduct assembly line testing of new vehicles and engines as well as to test emissions of in-use vehicles and engines after they have been introduced into commerce. This Information Collection Request covers inquiries directed at the owners/lessees of in-use light-duty motor vehicles to see if their specific vehicles are suitable for an EPA in-use testing investigation and the paperwork burdens attendant upon election to participate.

	The light-duty in-use testing program can be broken down into three closely related components. The first is the surveillance testing program, with the possibility of a confirmatory testing phase. The second component is a small program to test the functionality of onboard diagnostics (OBD) systems on in-use vehicles, which is simply additional testing on a subset of vehicles already recruited for the surveillance program. Finally, budget permitting, there are other occasional "special investigations" to address specific issues. An example of a special investigation might be procurement of a class of vehicles to test compatibility with a particular portable emissions monitoring (PEM) unit. Special investigations are like testing of that portion of surveillance classes that have been selected to address a specific informational need. EPA may or may not procure vehicles in the same way as for the surveillance and OBD programs. If the test vehicles are not procured from the public, the burden will not be accounted for in this collection request as burden to the public but may be reflected in the cost to the agency. The number of such tests will vary.

	Light-duty vehicle testing typically includes standard emissions test cycles and standard OBD tests performed at EPA's National Vehicle and Fuel Emissions Laboratory in Ann Arbor, Michigan. The primary purpose of these programs is informational: to give EPA and manufacturers intelligence regarding emissions performance of in-use vehicles. Manufacturers are involved at every step of the ongoing surveillance and confirmatory programs: they are informed of the emissions tests, can be present during vehicle preparation and testing, are given test results, and participate in post-failure investigations. The testing supplements information from the manufacturers' own discretionary in-use testing programs as well as the mandatory reporting under the manufacturers' In-Use Vehicle Program (IUVP) under 40 CFR §§1845 - 1847.

	The light-duty in-use testing program entails two formalized information collections. Participation in the information collections, as well as the vehicle evaluation, is strictly voluntary. (The actual solicitation of information is conducted by EPA's contractor.)  First, 25 to 50 owners/lessees of the vehicles of interest who are located within about 70 miles of Ann Arbor, Michigan are randomly selected from the owner list of vehicles obtained from the Michigan Secretary of State and sent a letter with a reply form and return envelope to accept or decline the invitation to participate.

 	Potential participants are offered monitory compensation for allowing their vehicles to be tested. The compensation is usually either twenty dollars per day and the use of a loaner vehicle or fifty dollars per day. Occasionally, if a class of vehicles is difficult to procure, the incentive may be increased.

	After a suitable time for response, positive respondents are considered for inclusion and are contacted in the order received until the required number of vehicles is identified. If the owner/lessee is reached and willing, a screening is conducted by telephone in which about 30 questions concerning vehicle condition and maintenance are asked. The first three owners who successfully complete the telephone screening provide the vehicles for the surveillance class. The vehicles are brought to EPA's NVFEL and tested. If there are any test failures in the first three vehicles, then two more are recruited in the same manner. Additional groups of potential participants will be contacted until the necessary number of vehicles has been obtained.

	The information collected is used to ensure that vehicles procured meet relevant criteria. For example, the vehicle must not have been tampered with or have other overt problems. Special testing investigations and particular types of vehicles may have additional or alternative criteria.

	Those who elect to participate are asked if they are willing to provide their maintenance records for copying. Doing so is voluntary and has no effect on eligibility. At the time of delivery or pick-up, participants go over the answers that they provided during the telephone screening and sign a notarized statement that the answers are correct. They sign a test agreement, a cash incentive form and, if elected by the participant, a loaner car agreement. Upon surrendering their vehicle, they sign a vehicle release.

	As part of the surveillance process, EPA attempts to determine the cause of any emissions test failures. Post-test "special maintenance" involves close examination of the vehicle, nearly always with manufacturer participation. This may produce relevant information about the cause of the failure. Surveillance test data are also supplemented with information from manufacturer's test data, EPA certification confirmatory test rest results, defect reports, service bulletins, CARB (California Air Resources Board) warranty reports, state Inspection/Maintenance (I/M) information, manufacturer service technician bulletins, and the results of the manufacturers' in-use vehicle tests submitted to EPA and any other in-use testing results. Manufacturers/importers are involved in the process from the outset and receive test results from the Federal Test Procedure (FTP), Highway, US06, evaporative and cold test procedures, including test failures. The process of identifying problems is collaborative and cooperative in nearly all cases.

	If EPA believes that a recall is indicated, and the manufacturer/importer agrees that EPA's conclusion is valid, it will agree to conduct a voluntary recall. However, if questions remain, EPA has procedures in place to run the confirmatory test phase with continued manufacturer involvement. Even at this stage the inferences are informational rather than statistical: to identify, based on engineering judgment, the appropriate population to which the problem applies, identify the cause of the problem, resolve issues regarding the testing protocols and results, etc.

	Based on information gathered from all sources, EPA can make an administrative finding mandating recall and repair of in-use vehicles if it determines that "a substantial number" of vehicles in a class or category do not comply with the emissions requirements as a result of its own in-use testing program. This determination will be based on information from a variety of sources that may or may not include EPA in-use testing. Such findings are subject to the Administrative Procedures Act and are reviewable in court under the "substantial evidence" test (5 USC §706(2)(E)), which is restated in the "substantial evidence" standard in the Clean Air Act for ordering recalls.

	Procurement of light duty vehicles for a confirmatory testing phase is similar to that for the surveillance phase, except that participants whose vehicles had been in the surveillance phase are screened out and owners are asked more questions about their vehicle's use and maintenance.

	During fiscal year 2018, the most recent year with complete information, 119 surveillance vehicle in-use testing actions were conducted by EPA. No OBD actions or special vehicle investigations were conducted. Eight confirmatory testing actions were conducted for a total of 127 testing actions. This corresponds to 993 contacts and 140 telephone interviews and/or other follow-up participant contacts. This collection imposes a burden of 228 hours annually. This collection has no respondent recordkeeping requirements.

Section 2: Need for and Use of the Collection

2(a) Need/Authority for the Collection

	Under Title II of the Clean Air Act, (42 U.S.C. §7521 et seq.), manufacturers of motor vehicles and engines are required to design and build vehicles which will comply with emission standards throughout their useful lives. ("Useful life" is defined by statute and regulation; it varies by type of vehicle or engine.)  Pursuant to section Clean Air Act section 207(c) (42 USC §7541), EPA is responsible for monitoring compliance and investigating possible noncompliance with emission standards.

	To fulfill this function, it is necessary for EPA to test actual "in-use" vehicles; these vehicles must be obtained from their owners/lessees. As part of the procurement process, EPA must determine that the vehicle is within the useful life and that it has been "properly maintained and used". In order to do this, EPA must make a limited inquiry of the owner/lessees who are willing to participate; EPA uses the Surveillance and Confirmatory Telephone Questionnaires (EPA forms 5900-305 and 5900-308, respectively) to determine the suitability of the vehicles.

2(b) Practical Utility/Users of the Data

	EPA needs the information from the vehicle owner/lessee to determine that the vehicle is within its "useful life" and that it has been "properly maintained and used."  EPA's Compliance Division, Office of Transportation and Air Quality, is the prime user of this information. Manufacturers whose models are being tested receive the vehicle identification number (VIN) of the vehicle to be tested. Manufacturers are informed of pre-test maintenance and test dates and receive test results. They also participate in post-test "special maintenance" to investigate failures.

Section 3:  Nonduplication, Consultations, and Other Collection Criteria

3(a) Nonduplication

	The information obtained from the vehicle owner/lessee is unique to that specific vehicle; it is not obtainable from any other source. There is no other information available, in either public or private databases that will adequately serve the program purposes. (Some vehicle maintenance information, such as warranty repairs and scheduled maintenance done at dealers' outlets, is available from manufacturers and commercial automotive data services, and such information may be supplied by manufacturers in their own interests or as queried by EPA. However, it is not a substitute for owners'/lessees' own records.) Additionally, there are no other similar government programs which would allow sharing of data.

3(b) Public Notice Prior to ICR Submission to OMB

	EPA will solicit public comment by means of a Federal Register Notice.

3(c) Consultations

	In preparing this ICR, EPA consulted with two of its contractor's employees, Mr. David Knott,<PHONE_NUMBER>, and Ms. Kim Cieslak. (EPA's contractor procures and maintains in-use passenger cars and light duty trucks.). Ms. Cieslak mails out the procurement letters and conducts the telephone interviews; she was asked to monitor how much time the interviews required. She determined the average to be 20 minutes per telephone interview for the surveillance screening and 50 minutes for the confirmatory screening. She also estimated that  approximately 90% of telephone questionnaires result in the procurement of a vehicle. David Knott is her supervisor.  He consulted with technicians who work with participants and observe the length of time it takes for them to fill out forms when the vehicles are picked up by Jacobs and returned to the participant.

3(d) Effects of Less Frequent Collection

	Information is collected only once per vehicle evaluation; less frequent collection is not possible. Less frequent information collection for the in-use testing program would make it challenging for EPA to verify manufacturers' compliance with Title II of the Clean Air Act, (42 U.S.C. §7521 et seq.)

3 (e) General Guidelines

	This information collection activity complies with the requirements of 5 CFR 1320.5(d)(2).

3 (f) Confidentiality

 	Information gathered from light-duty vehicle respondents is stored in contractor files. These records, including names and social security numbers needed for those who accept payment over $599, are completely segregated from test results which are separately handled and stored by EPA. Respondent information is handled and stored by the contractors and two EPA representatives. It is not available to the public. Test results are tracked by vehicle control number and are shared with manufacturers by email automatically; they are available to the public. This information collection has completed a Privacy Impact Assessment, which has been approved by EPA's privacy office. The system has been assigned System of Records EPA-60.

3(g) Sensitive Questions

	No sensitive questions are asked in this information collection.

Section 4. Respondents and Information Requested

4(a) Respondents/SIC & NAICS Codes

	The respondents are individual vehicle owners/lessees of any vehicle regulated by EPA under the Clean Air Act (No NAICS code).

4(b) Information Requested

(i) Data items

	Respondents who receive EPA's initial request are asked to supply the following information on the Reply Form (EPA form 5900-306) via a postage paid return envelope; participation is entirely voluntary:

 If they own/lease the desired vehicle - verify the make and model
 Current odometer reading
 Are they the original owner/lessee
 Transmission type
 Are they interested in participating
 Provide contact information

	Those who indicate they wish to be considered for participation are asked for additional information in the telephone questionnaires:

 Has the odometer malfunctioned and, if so, how long was it inoperative?
 Has the vehicle catalyst ever been replaced?
 Do they have maintenance records; would they allow EPA to review and copy them?

	There are no recordkeeping requirements associated with this collection.

(ii) Respondent Activities

	Responses to the request for participation and information collection are strictly voluntary.

	Those wishing to participate are asked to fill out a postage-paid information form. Some are then contacted by telephone to obtain the additional information listed above. Vehicles that will be evaluated are brought to EPA's National Vehicle and Fuel Emissions Laboratory (NVFEL) for testing by the vehicle owner or a contractor. The owners/lessees receive a cash incentive for each day EPA keeps the vehicle or a lesser cash incentive and, if requested, a late model loaner car with a full tank of gas and unlimited mileage for the duration of the testing, which usually takes two to four weeks.

	Most of the information requested is known by the owner/lessee; some information might have to be obtained by simple vehicle or engine inspection or by reference to maintenance records (if available).

Section 5: The Information Collected--Agency Activities, Collection Methodology, and Information Management

5(a) Agency Activities

	Agency staff typically have no involvement in gathering the information, as that task is done by an EPA contractor.  However, on occasion, staff are required to answer specific questions that arise during the information gathering process. Agency staff may review the final telephone screening questions and answers for completeness as well as potential issues relevant to the vehicle being evaluated. Agency staff select the vehicle classes to be tested, view test results, and participate in discussions with manufacturers relating to the testing preparations and results.

5(b) Collection Methodology and Management

	Information is obtained via mailed responses and telephone interviews; it is stored in a vehicle file. The information is reviewed to see if the specific vehicle or engine meets the criteria for evaluation. The file is typically maintained for 10 years and then destroyed.

5(c) Small Entity Flexibility

	The information requested is completely voluntary and imposes no mandatory burden on any respondent. The information collected is the minimum necessary to assure that vehicles meet the criteria for evaluation. Therefore, there is no additional need to reduce the burden on small entities.

5(d) Collection Schedule

	Information is collected on a continuous basis. The number of solicitations mailed out in a given timeframe is a function of available test capacity and how difficult a particular vehicle type is to procure.

Section 6 Estimating the Burden and Cost of the Collection

6(a) Estimating Respondent Burden

	As explained above, EPA's contractor estimated that each telephone screening interview takes, on average, approximately 20 minutes for the surveillance screening and 50 minutes for the confirmatory screening. Subsequent information-related burdens for participants (such as reviewing and attesting to the telephone screening answers and supplying maintenance records voluntarily) upon delivery of light-duty vehicles, is estimated at 40 minutes. We estimate that the initial contact burden by letter to average five minutes. The total response burden is estimated to be 228 hours annually.

6(b) Estimating Respondent Costs

(i) Estimating labor costs

	There is no typical individual owner/lessee; they represent the average person who acquires or owns a vehicle or engine. For this analysis we assume a cost of $25.72 per hour, based on the mean hourly wage for All Occupations, from the Bureau of Labor Statistics, May 2019 National Occupational Employment and Wage Estimates, United States, (https://www.bls.gov/oes/current/oes_nat.htm#00-0000, accessed September 20, 2020).
The annual labor cost is therefore $5,864.

(ii) Estimating Capital and Operations and Maintenance Costs

	This collection has no capital, operations or maintenance costs.

(iii) Start-up Costs

	This collection has no start-up costs.

6(c) Estimating Agency Burden

	EPA uses contractor employees to recruit all of the vehicles and collect essentially all of the information covered by this information collection request. The contractor is responsible for, among other things, sending out invitation letters, contacting responders, getting the vehicles, preparing the vehicles for tests, returning the vehicles to the owners, paying the monitory compensation to participants and maintaining a fleet of about nine vehicles that will be loaned to participants while their vehicles are being tested. The average annual contractor costs for the light-duty surveillance and confirmatory testing was approximately $764,000. An estimated 1.5 EPA employees oversee the programs at an annual cost of $228,540 ($152,360 is the average cost for a full-time employee in the Office of Transportation and Air Quality.) The total estimated Agency cost is about $992,540 per year.

6(d) Estimating the Respondent Universe and Total Burden and Costs

	From the above discussion the following total burden and cost estimates can be calculated as presented below.

6(e) Bottom Line Burden Hours and Cost

(i) Respondent Tally

Program
Vehicles
Initial Contacts (1)
Burden @ 5 min ea.(min)
Participant Contacts (2)
Burden @ 60 min ea (min)
Light Duty Surveillance
                                                                            119
                                                                              -
                                                                              -
                                                                            131
                                                                          7,860
Onboard Diagnostics Surveillance
                                                                              0
                                                                              0
                                                                              0
                                                                              0
                                                                              0
Special Vehicle Investigation
                                                                              0
                                                                              0
                                                                              0
                                                                              0
                                                                              0

                                                       Burden @ 90 min ea (min)
Light Duty Confirmatory
                                                                              8
                                                                              -
                                                                              -
                                                                              9
          810
Totals
                                                                            127
                                                                            993
                                                                          4,965
                                                                            140
                                                                          8,670
Burden Hours

                                                                             83

                                                                            145
Total Burden

                                                                            228
(1) The Initial Contacts total includes responses for both Light Duty Surveillance and Confirmatory programs
(2) Approximately 90% of contacts do not result in a procured vehicle.

There are no respondent, operating, capital, or startup costs associated with this collection.

(ii) Agency tally

Employees	 	1.5 (Involved in the light-duty vehicle in-use testing program)
Employee Cost	$228,540
Contract Cost		$764,000
Total Cost    	          	$992,540

6(f) Reasons for change in burden

	The changes in burden to the public from the burden calculated for the previous iteration of this Information Collection Request are a decrease in initial contacts from 1,627 to 993.  Also, the total number of vehicles recruited decreased which correspond to a decrease in 74 hours and a total decrease in burden cost to the public of $1,342. These changes are due to many different factors. Although the number of invitations sent out rises each year, the number of responses that we receive has decreased. The two factors to which the decreases are most attributed are 1) invitations are discarded as junk mail and 2) owner's concern that the invitation is a scam.  Some other factors may be that the incentive is not enough for people to go through the trouble of volunteering for the program or that the vehicles that we are trying to recruit may be more expensive vehicles and, therefore, the owners are less likely to want to volunteer their vehicles for testing. Also, EPA selected vehicle families that were older and were more difficult to procure.  This resulted in less vehicles procured during these years.  We believe that because of these reasons the number of responses and, therefore the burden to the public, has decreased.

	Special vehicle investigations were previously done to study known in-use concerns that were identified in classes of vehicles (for example, older vehicles or a specific model.)  In the years since 2016 there have been special investigations, but the vehicles were not obtained from the public. Instead they were procured though EPA's contractor or from manufacturers. Therefore, the information collection burden on the public was decreased to zero for special investigations. The burden instead was transferred to contractors or EPA employees.

	It should be noted that EPA has not conducted any Onboard Diagnostic Surveillance resulting in no burden due to that program.

	One small change has been made to EPA form 5900-308, Confirmatory Screening Tool.  The reporting burden statement has been updated to include the same estimate as the other forms, which is more accurate.  This change does not affect any of the calculations or estimates above.

6(g) Burden Statement

	The annual public reporting and recordkeeping burden for this collection of information is estimated to average approximately 228 hours per year; less than one hour on average for each owner/lessee who receives a solicitation to participate.  This estimate includes the time to review the solicitation material, complete the reply correspondence, complete the telephone screening for the subset contacted, and complete paperwork for delivery and pickup of participating vehicles and for monetary compensation. Participation is completely voluntary. Burden means the total time, effort, or financial resources expended by persons to generate, maintain, retain, or disclose or provide information to or for a federal agency. This includes the time needed to review instructions; develop, acquire, install, and utilize technology and systems for the purposes of collecting, validating, and verifying information, processing and maintaining information, and disclosing and providing information; adjust the existing ways to comply with any previously applicable instructions and requirements; train personnel to be able to respond to a collection of information; search data sources; complete and review the collection or sponsor, and a person is not required to respond to, a collection of information unless it displays a currently valid OMB control number. The OMB control numbers for EPA's regulation are listed in 40 CFR part 9 and 48 CFR chapter 15.

	To comment on the Agency's need for this information, the accuracy of the provided burden estimates, and any suggested methods for minimizing respondent burden, including the use of automated collection techniques, EPA has established a public docket for this ICR under Docket ID Number EPA-HQ-OAR-2010-0690, which is available for online viewing at www.regulations.gov, or in person viewing at the EPA Docket Center, EPA/DC, WJC West, Room 3334, 1301 Constitution Ave., NW, Washington, DC. The Public Reading Room is open from 8:30 a.m. to 4:30 p.m., Monday through Friday, excluding legal holidays. The telephone number for the Public Reading Room is (202) 566 - 1744. An electronic version of the public docket is available at www.regulations.gov. This site can be used to submit or view public comments, access the index listing of the contents of the public docket, and to access those documents in the public docket that are available electronically. When in the system, select "search," then key in the Docket ID Number identified above. Also, you can send comments to the Office of Information and Regulatory Affairs, Office of Management and Budget, 725 17th Street, NW, Washington, D.C. 20503, Attention: Desk Officer for EPA. Please include the EPA Docket ID Number EPA-HQ-OAR-2010-0690 and OMB Control Number 2060-0086 in any correspondence.


[Federal Register Volume 76, Number 34 (Friday, February 18, 2011)]
[Notices]
[Pages 9583-9584]
[FR Doc No: 2011-3679]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-D-0082]

Draft Guidance for Industry on Clinical Pharmacogenomics:
Premarketing Evaluation in Early Phase Clinical Studies; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the
availability of a draft guidance for industry entitled ``Clinical
Pharmacogenomics: Premarketing Evaluation in Early Phase Clinical
Studies.'' The draft guidance is intended to assist the pharmaceutical
industry and other investigators engaged in new drug development in
evaluating how variations in the human genome could affect the clinical
pharmacology properties and clinical responses of drugs.

DATES: Although you can comment on any guidance at any time (see 21 CFR
10.115(g)(5)), to ensure that the Agency considers your comment on this
draft guidance before it begins work on the final version of the
guidance, submit either electronic or written comments on the draft
guidance by April 19, 2011.

ADDRESSES: Submit written requests for single copies of the draft
guidance to the Division of Drug Information, Center for Drug
Evaluation and Research, Food and Drug Administration, 10903 New
Hampshire Ave., Bldg. 51, rm. 2201, Silver Spring, MD 20993-0002 or the
Office of Communication, Outreach and Development (HFM-40), Center for
Biologics Evaluation and Research (CBER), Food and Drug Administration,
1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448. Send one
self-addressed adhesive label to assist that office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the guidance document.
    Submit electronic comments on the draft guidance to http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane,
rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT:

Lawrence J. Lesko, Center for Drug Evaluation and Research, Food and
Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 3178,
Silver Spring, MD 20993-0002,<PHONE_NUMBER>; or
Shiew-Mei Huang, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 3188, Silver
Spring, MD 20993-0002,<PHONE_NUMBER>; or
Stephen Ripley, Center for Biologics Evaluation and Research, Food and
Drug Administration (HFM-17), 1401 Rockville Pike, suite 200N,
Rockville, MD 20852-1448,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    FDA is announcing the availability of a draft guidance entitled
``Clinical Pharmacogenomics: Premarketing Evaluation in Early Phase
Clinical Studies.'' Pharmacogenomics (PGx) broadly refers to the study
of variations of DNA and RNA characteristics and their relation to drug
exposure and/or response. Drug exposure refers to either the
administered dose or levels in a body tissue or fluid (e.g., blood,
plasma, cerebrospinal fluid). Drug response results from the interplay
of pharmacokinetics (e.g., drug absorption, metabolism, and excretion),
and pharmacodynamics (i.e., all of the effects of the drug on various
physiologic and pathologic processes, including effectiveness and
adverse effects). Genetic variations can also influence the exposure-
response (E/R) relationship of drugs. PGx studies can enhance the
understanding of interindividual differences in the efficacy and safety
of investigational drugs.
    Drug development is commonly described as going through ``phases''
(21 CFR 312.21). The first two phases collect information about safety
and dosing, so that the larger, later (phase 3) studies (the adequate
and well-controlled studies needed to support marketing approval) can
gather the additional information about effectiveness and safety that
is needed to evaluate the overall benefit-risk relationship of the drug
and to provide an adequate basis for physician labeling. Much of the
genomic information collected and assessed during the early phases is
often described as ``exploratory.'' Phase 2 studies that suggest
genomic influences can lead to phase 3 trials that incorporate findings
into prespecified hypotheses, such as enriching the study with
genomically defined individuals, determining dose based on demonstrated
variability in earlier studies, and defining a priori hypothesis
testing of a primary endpoint in a genomic subset.
    PGx information obtained from genomic investigations during the
course of drug development (and from postmarketing studies) can improve
the effectiveness and safety of drugs by identifying patients at high
risk for a serious adverse event or absence of benefit; improving the
benefit/risk relationship of drugs by using genomic tests to identify
patients most likely to respond, or unable to respond to a drug; and by
helping to select optimal doses based on genotype-driven differences in
PK (pharmacodynamics) and/or PD (pharmacodynamics) of a drug. An
important prerequisite to successful use of genetic information in drug
development is appropriate collection and storage of DNA samples from
all clinical trials, both exploratory and the adequate and well-
controlled studies intended to support effectiveness and safety.
    This draft guidance is being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). The draft guidance
represents the Agency's current thinking on conducting pharmacogenomic
studies in

early phase clinical studies. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public. An
alternative approach may be used if such approach satisfies the
requirement of the applicable statutes and regulations.

II. Paperwork Reduction Act of 1995

    This draft guidance refers to previously approved collections of
information that 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 201.57 have been
approved under OMB control number 0910-0572.

III. Comments

    Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. It is no
longer necessary to send two copies of mailed 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.

IV. Electronic Access

    Persons with access to the Internet may obtain the document at
either http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances, or http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances, or http://www.regulations.gov.

    Dated: February 14, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-3679 Filed 2-17-11; 8:45 am]
BILLING CODE 4160-01-P