[Federal Register Volume 84, Number 79 (Wednesday, April 24, 2019)]
[Proposed Rules]
[Pages 17116-17124]
[FR Doc No: 2019-08260]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 878

[Docket No. FDA-2019-N-1250]

General and Plastic Surgery Devices; Reclassification of Certain
Surgical Staplers

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed order.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or the Agency) is
proposing to reclassify surgical staplers for internal use (currently
regulated under the classification for ``manual surgical instrument for
general use'' and assigned the product code GAG) from class I (general
controls) into class II (special controls) and subject to premarket
review. FDA is identifying the proposed special controls for surgical
staplers for internal use that the Agency believes are necessary to
provide a reasonable assurance of the safety and effectiveness of the
device. FDA is proposing this reclassification on its own initiative
based on new information. As part of this reclassification, FDA is also
proposing to amend the existing classification for ``manual surgical
instrument for general use'' to remove staplers and to create a
separate classification regulation for surgical staplers that
distinguishes between surgical staplers for internal use and external
use.

DATES: Submit either electronic or written comments on the proposed
order by June 24, 2019. Please see section XI of this document for the
proposed effective date of any final order that may publish based on
this proposed order.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before June 24, 2019. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of June 24, 2019. Comments received
by mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal Rulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2019-N-1250 for ``General and Plastic Surgery Devices;
Reclassification of Certain Surgical Staplers.'' Received comments,
those filed in a timely manner (see ADDRESSES), will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://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 Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: R. Dale Rimmer, Center for Devices and
Radiological Health, Food and Drug Administration, 10903 New Hampshire
Ave., Bldg. 66, Rm. G425, Silver Spring, MD 20993,<PHONE_NUMBER>,
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background--Regulatory Authorities

    The Federal Food, Drug, and Cosmetic Act (FD&C Act), as amended,
establishes a comprehensive system for the regulation of medical
devices intended for human use. Section 513 of the FD&C Act (21 U.S.C.
360c) established three categories (classes) of devices, reflecting the
regulatory controls needed to

provide reasonable assurance of their safety and effectiveness. The
three categories of devices are class I (general controls), class II
(special controls), and class III (premarket approval).
    Section 513(a)(1) of the FD&C Act defines the 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 section 501,
502, 510, 516, 518, 519, or 520 (21 U.S.C. 351, 352, 360, 360f, 360h,
360i, or 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 which 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 general controls by themselves are insufficient to provide
reasonable assurance of safety and effectiveness, and for which there
is sufficient information to establish special controls to provide such
assurance, including the promulgation 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). Class III devices are those devices for
which insufficient information exists to determine that general
controls and special controls would provide a reasonable assurance of
safety and effectiveness, and which are purported or represented to be
for a use in supporting or sustaining human life or for a use which is
of substantial importance in preventing impairment of human health, or
which present a potential unreasonable risk of illness or injury
(section 513(a)(1)(C) of the FD&C Act).
    Under section 513(d)(1) of the FD&C Act, devices that were in
commercial distribution before the enactment of the 1976 amendments
(Medical Device Amendments of 1976, Pub. L. 94-295), May 28, 1976
(generally referred to as ``preamendments devices''), are classified
after FDA has: (1) Received a recommendation from a device
classification panel (an FDA advisory committee); (2) published the
panel's recommendation for comment, along with a proposed regulation
classifying the device; and (3) published a final regulation
classifying the device. FDA has classified most preamendments devices
under these procedures.
    Devices that were not in commercial distribution before May 28,
1976 (generally referred to as ``postamendments devices''), are
automatically classified by section 513(f)(1) of the FD&C Act into
class III without any FDA rulemaking process. Those devices remain in
class III and require premarket approval, unless, and until: (1) FDA
reclassifies the device into class I or II or (2) FDA issues an order
finding the device to be substantially equivalent, in accordance with
section 513(i) of the FD&C Act, to a predicate device that does not
require premarket approval. The Agency determines whether new devices
are substantially equivalent to previously marketed devices by means of
premarket notification procedures in section 510(k) of the FD&C Act and
part 807, subpart E of the regulations (21 CFR part 807).
    On July 9, 2012, Congress enacted the Food and Drug Administration
Safety and Innovation Act (FDASIA) (Pub. L. 112-144). Section 608(a) of
FDASIA amended section 513(e) of the FD&C Act, changing the process for
reclassifying a device from rulemaking to an administrative order.
Section 513(e)(1)(A)(i) of the FD&C Act sets forth the process for
issuing a final order. Specifically, prior to the issuance of an
administrative order reclassifying a device, the following must occur:
(1) Publication of a proposed reclassification 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. The proposed reclassification order must 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, and the nature and
incidence (if known) of the risks of the device.
    Section 513(e)(1)(A)(i) provides that FDA may, by administrative
order, reclassify a device based on ``new information.'' FDA can
initiate a reclassification under section 513(e) or an interested
person may petition FDA. 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 Dep't of Health, Educ. & Welfare, 587 F.2d 1173, 1174 n.1
(D.C. Cir. 1978); Upjohn Co. 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, 366 F.2d 177, 181 (7th Cir. 1966)) or in light of
changes in ``medical science'' (see Upjohn Co. v. Finch, 422 F.2d 944,
951 (6th Cir. 1970)). Whether data before the Agency are old or new,
the ``new information'' to support reclassification under section
513(e) of the FD&C Act must be ``valid scientific evidence'', as
defined in section 513(a)(3) of the FD&C Act and 21 CFR 860.7(c)(2).
(See, e.g., 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)).
    FDA relies upon ``valid scientific evidence'' in the classification
process to determine the level of regulation for devices. 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 (see section 520(c) of the FD&C Act).
    Section 510(m) of the FD&C Act provides that a class II device may
be exempted from the premarket notification requirements under section
510(k) of the FD&C Act if the Agency determines that premarket
notification is not necessary to assure the safety and effectiveness of
the device. FDA has determined that premarket notification is necessary
to reasonably assure the safety and effectiveness of surgical staplers
for internal use. Therefore, the Agency does not intend to exempt this
proposed class II device from premarket notification (510(k))
submission as provided under section 510(m) of the FD&C Act.

II. Regulatory History of the Devices

    Surgical staplers were classified in part 878 (21 CFR part 878) in
a final rule published in the Federal Register on June 24, 1988 (53 FR
23856), that classified 51 general and plastic surgery devices. This
1988 rule classified staplers into class I (general controls).

These devices were grouped with other devices under ``Manual surgical
instrument for general use'' in Sec.  878.4800 (21 CFR 878.4800). At
the time, surgical staplers had been in common use in medical practice
for many years, and FDA believed that general controls were sufficient
to provide reasonable assurance of the safety and effectiveness of
those devices. This rule was amended on April 5, 1989 (54 FR 13826), to
clarify that manual surgical instruments for general use, Sec.
878.4800, made of the same materials as used in the preamendments
devices were exempt from premarket notification (510(k)) review.
    On December 7, 1994, FDA further amended the classification when it
published a final rule in the Federal Register (59 FR 63005) that
exempted 148 class I devices from premarket notification, with
limitations. Surgical staplers were one of those exempted devices. FDA
determined that manufacturers' submissions of premarket notifications
were unnecessary for the protection of the public health and that FDA's
review of such submissions would not advance its public health mission.
    On March 8, 2019, FDA issued a letter to healthcare providers to
inform them of the risks associated with misuse of surgical staplers
and to provide recommendations for reducing the risk of adverse events
associated with these devices (Ref. 1). This letter recommends that
users carefully follow the stapler manufacturer's instructions for use
and provides additional recommendations for selecting the appropriate
staple sizes and tissue types appropriate for use with the stapler.
    Elsewhere in this issue of the Federal Register, FDA is publishing
a notice of availability for a draft guidance entitled ``Surgical
Staplers and Staples for Internal Use--Labeling Recommendations; Draft
Guidance for Industry and Food and Drug Administration Staff.'' As
identified in this draft guidance, FDA has become aware of a large
number of adverse events associated with surgical staplers and staples
for internal use. This draft guidance communicates FDA's
recommendations for contraindications, warnings, directions for use,
and technical characteristics and performance parameters to be included
in the product labeling to help promote the safe and effective use of
surgical staplers and staples for internal use. This draft guidance
also provides recommendations for content to be included in the package
labels, so that users may easily look at the label and obtain critical
information necessary for proper device selection.
    Surgical staples are currently regulated as class II devices under
21 CFR 878.4750 (Implantable staple) and are subject to premarket
notification (510(k)) review. FDA does not intend to change the
classification of surgical staples at this time and they are outside
the scope of this reclassification action.

III. Device Description

    A surgical stapler is a specialized prescription device used to
deliver compatible staples during surgery. Prescription devices are
exempt from the requirement for adequate directions for use for the
layperson under section 502(f)(1) of the FD&C Act and 21 CFR 801.5, as
long as the conditions of 21 CFR 801.109 are met.
    To delineate between surgical staplers and their intended uses, FDA
has identified two subsets of surgical staplers: (1) Surgical staplers
for internal use and (2) surgical staplers for external use.
    A surgical stapler for internal use is a specialized prescription
device used to deliver compatible staples to internal tissues during
surgery for removing part of an organ (i.e., resection), cutting
through organs and tissues (i.e., transection), and creating
connections between structures (i.e., anastomoses). It may be used in
open, minimally invasive, and endoscopic surgery. Surgical staplers for
internal use may be indicated for use in a wide range of surgical
applications, including, but not limited to, gastrointestinal,
gynecologic, and thoracic surgery.
    Many types of surgical staplers for internal use exist, including,
but not limited to, linear non-cutting staplers, transverse
approximating staplers, transverse anastomoses staplers,
gastrointestinal anastomoses linear cutting (articulating and non-
articulating) staplers, and circular (i.e., end-to-end anastomoses)
staplers. Surgical staplers for internal use include both manual and
powered staplers.
    A surgical stapler for external use is a specialized prescription
device used to deliver compatible staples to skin during surgery. FDA
is proposing to reclassify internal staplers only; external staplers
will remain class I, exempt from premarket review.

IV. Proposed Reclassification

    FDA is proposing to reclassify surgical staplers for internal use
from class I (general controls), exempt from premarket review, to class
II (special controls), subject to premarket review. FDA believes that
general controls by themselves are insufficient to provide reasonable
assurance of safety and effectiveness for these devices, and that there
is sufficient information to establish special controls to provide such
assurance. In accordance with section 513(e)(1)(A)(i) of the FD&C Act,
FDA, on its own initiative, is proposing to reclassify these devices
based on new information. The process for issuing a final order for
reclassification of a device from class I to class II pursuant to
section 513(e) of the FD&C Act is provided in 21 CFR 860.130 of the
regulations. Specifically, prior to the issuance of a final order
reclassifying a device, the following must occur: (1) Publication of a
proposed reclassification 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. The
Commissioner of Food and Drugs is required to consult with a
classification panel and may secure a recommendation with respect to
the reclassification of the device. FDA will consult with the panel
regarding the reclassification of the device in accordance with the
procedures set forth in 21 CFR 860.125 and intends to secure the
panel's recommendation. If FDA issues a final order, the Agency will
publish the panel's recommendation in the Federal Register when the
Agency publishes the final order.
    FDA is also proposing to revise Sec.  878.4800 (Manual surgical
instrument for general use) to remove staplers and to create a separate
classification regulation in part 878 for surgical staplers that
distinguishes between surgical staplers for internal use and external
use.

V. 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
concerning the proposed reclassification including the public health
benefit of the use of surgical staplers for internal use, and the
nature, and if known, the incidence of the risk of the devices, as
discussed in section VI of this proposed order.
    Surgical staplers for internal use provide benefit to the public
health by facilitating surgical procedures and allowing for shorter
surgical procedure times compared to manual suturing.
    FDA has evaluated the risks to health associated with the use of
surgical staplers for internal use and has identified the following
risks for this device:

     Complications associated with device failure/malfunction.
Device failures or malfunctions may result in prolonged surgical
procedures, unplanned surgical interventions, and other complications
such as bleeding, sepsis, fistula formation, tearing of internal
tissues and organs, increased risk of cancer recurrence, and death.
     Complications associated with use error/improper device
selection and use. Use error may result from a device design that is
difficult to operate and/or labeling that is difficult to comprehend.
For example, user difficulty in firing the stapler may result in
staples not being fully deployed, and misfiring may result in staples
being inadvertently applied to the wrong tissue. Inadequate
instructions for use may result in selection of incorrectly sized
staples for the target tissue. When staples are applied to the wrong
tissue or when incorrectly sized staples are applied, staples are
unable to properly approximate the underlying tissue, resulting in
tissue damage, anastomotic leakage, and bleeding. This in turn, may
lead to more severe complications, such as abscess, sepsis,
peritonitis, hemorrhage, or death.
     Adverse tissue reaction. If the patient-contacting
materials of the device are not biocompatible, local tissue irritation
and sensitization, cytotoxicity, or systemic toxicity may occur when
the device contacts sterile tissue.
     Infection. If the device is not adequately reprocessed or
sterilized, the device may introduce pathogenic organisms into sterile
tissue and may cause an infection in a patient.
    As discussed further in this document, these findings regarding the
public health benefits and risks to health associated with surgical
staplers for internal use are based on publicly available information,
including Medical Device Reporting (MDR) analyses, recalls, and the
published literature.

VI. Summary of Data Upon Which the Reclassification Is Based

    Surgical staplers for internal use have been shown to provide
several benefits over manual suturing, including reduction in surgical
time, reduced tissue trauma/manipulation, reduction in surgical
contamination by intestinal contents, and simple closure of vessels
and/or tissues (Ref. 2); however, they have also been associated with
numerous adverse events.
    As discussed below, based on a review of the MDR database, recalls
database, and the published scientific literature, there have been many
malfunctions and other problems associated with surgical staplers for
internal use, and some of these malfunctions or other problems have
been associated with serious complications, including death.
    Because surgical staplers are used together with staples as a
system, a search of the MDR database was conducted for both surgical
staplers for internal use under product code GAG (Stapler, Surgical)
and surgical staples for internal use under product code GDW (Staple,
Implantable) to obtain a comprehensive picture of the safety profile
for surgical staplers for internal use. From January 1, 2011, to March
31, 2018, FDA received over 41,000 individual MDRs for surgical
staplers and staples for internal use, including 366 deaths, over 9,000
serious injuries, and over 32,000 malfunctions. Some of the most
commonly reported problems in these adverse event reports include an
opening of the staple line or malformation of staples, misfiring,
difficulty in firing, failure of the stapler to fire the staple, and
misapplied staples (e.g., user applying staples to the wrong tissue or
applying staples of the wrong size to tissue). Although the majority of
the adverse events were reported under product code GDW, FDA believes
that many of the problems identified in these reports can be primarily
attributed to surgical staplers for internal use, since proper staple
formation is largely contingent on proper function and use of the
stapler.
    Of the 366 deaths, the cause of death was associated with an
opening of the staple line or malformation of staples in 159 reports,
bleeding during surgery in 53 reports, sepsis in 47 reports,
peritonitis in 5 reports, necrosis in 5 reports, and air embolism in 4
reports. Additionally, of the 366 deaths, 195 reports included
misfiring, difficulty in firing, and/or misapplied staples. Common
reasons cited for these problems included mechanical issues with the
device (e.g., mechanical jams), broken device components, and the
device operating differently than the user expected (e.g., different
force needed to deploy the device than expected). In 11 of the 366
deaths, use error was determined to be a contributing factor to the
death. Many of the same complications that resulted in death (e.g.,
bleeding during surgery, peritonitis, and sepsis) were also reported in
the serious injury reports; additional complications commonly reported
in the serious injury reports included tissue damage, organ perforation
or dehiscence, fistula formation, infection, hernia, and pain.
    The majority of staplers reported in these adverse events were
linear staplers, including articulating and curved tip linear staplers,
followed by circular staplers. Of the 366 deaths, 262 deaths were
reported for linear staplers while 63 were reported for circular
staplers; of the remaining 41 deaths, a type of stapler was not
identified in the MDR. The staplers involved in these adverse events
spanned a variety of different manufacturers; there were no distinct
differences between manufacturers and the reported causes of death.
    Of the 41,000 individual MDRs, over 32,000 MDRs were received for
malfunctions, under either the product code GAG (Stapler, Surgical) or
product code GDW (Staple, Implantable). The most common device-related
malfunctions included failure of the stapler to fire the staple,
failure to form staples, difficulty of opening/closing the stapler,
stapler misfiring, and stapler breakage. The most commonly reported
patient consequences from malfunctions with surgical staplers for
internal use included a delay in surgical procedure, hemorrhage, and
tissue damage. It should be noted that some patient consequences may
not be limited to a single reporting category of death, serious injury,
or malfunction. For example, a malfunction could result in sepsis,
which could lead to other serious injury and later death.
    The types and incidence of malfunctions and clinical consequences
to patients seen in the adverse event reports are also corroborated by
the published literature. In a systematic review of 30 clinical studies
(Refs. 3 to 32), including randomized controlled trials and
observational studies, the occurrence of stapler malfunctions in these
studies ranged from incidents in 0 to 19.2 percent (median = 1.8
percent) of patients and 0.1 to 5.2 percent of deployments.
    Consistent with the malfunctions seen in the adverse event reports
received by FDA, the most common malfunctions reported in these
clinical studies were related to opening of the staple line or
malformation of staples. In these studies, malformed staples and/or
staple lines comprised 31.8 percent of the malfunctions, while missing
staples and/or staple lines not forming comprised 19.5 percent of the
malfunctions. Problems with stapler firing and/or stapler function were
also commonly reported. Device sticking, locking, and/or jamming
comprised 15.9 percent of the malfunctions, while stapler misfiring
comprised 10.3 percent of the malfunctions. Inability of the stapler to
cut through tissue comprised

3.1 percent of the malfunctions, while stapler breakage comprised 2.6
percent of all malfunctions. Finally, problems with the stapler
cartridge not loading properly comprised 2.1 percent of the
malfunctions. Although the majority of studies in the systematic
literature review did not report on the incidence of stapler problems
associated with use error, a prospective, single-arm study evaluating
use of a surgical stapler in gastrointestinal stapling applications
found that 3.5 percent of stapler deployments in the study (15 of 423
deployments) were attributed to use error (Ref. 10). Additionally, as
discussed further below, common causes for surgical complications
reported in the literature include use error.
    While 75.8 percent of the stapler malfunctions in these studies did
not result in any major consequences to the patient, 10.5 percent of
the malfunctions resulted in the need to convert to open surgery, while
9.7 percent of the malfunctions resulted in hemorrhage; 4.0 percent of
the malfunctions resulted in both hemorrhage and the need to convert to
open surgery. In addition, multiple studies suggest that surgical
stapler malfunctions are associated with a higher risk of
complications. In a retrospective study of 349 colorectal resections
using a circular stapler, surgeries with surgical stapler malfunctions
were found to have higher incidences of unplanned proximal diversions,
ileus, gastrointestinal bleeding, and blood transfusions (Ref. 27). In
a retrospective study of 1,174 patients undergoing liver transections
using a stapler device, surgeries with surgical stapler malfunctions
were found to have a higher likelihood of transfusion, higher median
blood loss, and higher odds of morbidity and mortality compared to
surgeries without stapler malfunctions (Ref. 28). Anastomotic leaks
from surgical stapler malfunctions have also been associated with an
increased risk of cancer recurrence (Refs. 33 to 35). Altogether, the
adverse event reports and published literature indicate that surgical
stapler malfunctions are not uncommon and may produce adverse outcomes
such as conversion to open surgery, bleeding, morbidity, and death.
    Common causes for surgical complications reported in the literature
also include the use of incorrectly sized staples for the tissue,
incorrect use of the device by the user, and improper use of the device
for the condition of the patient's tissues, which may result in
reoperation or prolonged hospitalization (Ref. 36). For example, early
postoperative anastomotic leak due to such device issues may result in
a septic patient with peritonitis, requiring immediate surgery with
diversion of stool into a stoma. Minor or delayed anastomotic leaks due
to such device issues may result in an intra-abdominal abscess
requiring surgical or other invasive drainage procedures, temporary
diversion of stool, and prolonged intravenous nutrition. These
complications commonly result in prolonged hospital stays (Ref. 37).
Altogether, the adverse event reports and published literature indicate
that surgical stapler for internal use use error may cause or
contribute to surgical complications, e.g., anastomotic leaks, abscess,
sepsis, peritonitis, and death.
    From November 1, 2002, to December 30, 2018, FDA received a total
of 168 recalls for surgical staplers and staples for internal use under
product codes GAG and GDW, including one class I recall and 167 class
II recalls. The class I recall was for a hemorrhoidal circular stapler
that may result in incomplete staple formation due to difficulty in
firing. Of the 167 class II recalls, the most common reasons for recall
included non-conforming device components or device design-related
issues that may result in incomplete staple formation, failure to form
a staple line, malformed staples, or difficulty in firing. Several
devices were also recalled due to a potential breach in sterility.
    FDA acknowledges that the available valid scientific evidence,
including the review of the MDR database, recalls database, and the
published literature, primarily discuss surgical staplers for internal
use, and not surgical staplers for external use. At this time, FDA does
not believe that available information suggests that reclassification
of surgical staplers for external use is necessary to maintain a
reasonable assurance of safety and effectiveness of these devices.
    Based on its review of the MDR database, recalls database, and the
published literature, FDA has tentatively determined that special
controls, in addition to general controls, are necessary to provide a
reasonable assurance of safety and effectiveness for surgical staplers
for internal use. FDA believes the establishment of special controls is
necessary to ensure that the risks to health are adequately mitigated
by an assessment of these devices through completion of performance
testing, usability and labeling comprehension testing, biocompatibility
evaluation, sterility and shelf-life testing, and adequate labeling. In
addition, FDA believes that design controls under 21 CFR 820.30 are
necessary to ensure that specified design requirements are met and to
ensure compatibility of surgical staplers for internal use with
staples. Therefore, FDA, on its own initiative, is proposing to
reclassify these devices from class I into class II (special controls)
subject to premarket review.

VII. Summary of Reasons for Reclassification

    Based on the information reviewed by FDA, including the valid
scientific evidence regarding the public health benefit and nature and
incidence of the risk of the devices discussed in section VI, FDA
tentatively concludes that special controls, in addition to general
controls, are necessary to provide a reasonable assurance of safety and
effectiveness for surgical staplers for internal use. Therefore, FDA
proposes to reclassify surgical staplers for internal use from class I
into class II (special controls).

VIII. Proposed Special Controls

    FDA believes that the following special controls, together with
general controls, are necessary and sufficient to mitigate the risks to
health described in section V (complications associated with device
failure/malfunction, complications associated with use error/improper
device selection and use, adverse tissue reaction, and infection) and
provide a reasonable assurance of safety and effectiveness for surgical
staplers for internal use.
    Both device misuse and device malfunctions are root causes of the
adverse events associated with use of surgical staplers for internal
use (Ref. 38). Device misuse may be exacerbated by inadequate
instructions for use and insufficient warnings or precautions in the
device labeling (Ref. 39). To mitigate the risks of tissue damage,
anastomotic leakage, and bleeding arising from use error or improper
device use, FDA believes that the labeling must include specific
instructions for device use, including procedures associated with
proper device use and measures for preventing device malfunction,
evaluating the appropriateness of the target tissue for stapling, and
evaluating the resultant staple line. To further mitigate these risks,
the labeling must also include appropriate warnings, contraindications,
and limitations needed for safe use of the device. To prevent stapler
malfunction (e.g., from stapler jamming, locking, sticking, or
misfiring), information on the staples with which the stapler is
compatible must be provided in the labeling, such as models of
compatible staples, cartridge colors/staple heights, staple rows per
cartridge, staple patterns, and

maximum and minimum tissue thicknesses for each staple type. To prevent
improper application of staples to target tissue, the recommended
tissues (e.g., tissue thicknesses and tissue types) on which the
stapler is intended to be used must be identified in the labeling.
Unless data demonstrates the safety of doing so, contraindications must
be identified regarding use of the device on tissues for which the risk
of stapling outweighs any reasonably foreseeable benefit due to known
complications, including the stapling of necrotic or ischemic tissues
and tissues outside of the labeled limits of tissue thickness. The
labeling must provide appropriate warnings regarding how to avoid known
hazards associated with device use, including avoidance of obstructions
to the creation of a staple line (e.g., clips) and the unintended
stapling of other anatomic structures; avoidance of clamping and
unclamping of delicate tissue structures (e.g., venous structures and
bile ducts) to prevent tissue damage; avoidance of use of the stapler
on large blood vessels, such as the aorta; establishing and maintaining
proximal control of blood vessels prior to stapling; appropriate
measures to take if a stapler malfunction occurs while applying staples
across a blood vessel, such as clamping or ligating the vessel before
releasing the stapler, while the stapler is still closed on the tissue;
and ensuring stapler compatibility with staples, unless information is
provided demonstrating that the warnings do not apply to a particular
device. Usability testing and a labeling comprehension study must
demonstrate that the clinician can correctly select and use the device
for its indicated use based on the information in the labeling.
    To mitigate the risk of complications associated with device
failure or device malfunction, adequate performance testing is needed
to ensure that the stapler with compatible staples performs as intended
under anticipated conditions of use. FDA believes that adequate
performance testing must include an evaluation of staple formation
characteristics in the maximum and minimum tissue thicknesses for each
staple type; measurement of the worst-case deployment pressures on
stapler firing force; and a measurement of staple line strength.
Performance testing must also demonstrate confirmation of staple line
integrity (e.g., through the absence of vertically contiguous malformed
staples), as well as in vivo confirmation of staple line hemostasis
following staple deployment.\1\
---------------------------------------------------------------------------

    \1\ FDA supports the principles of the ``3Rs,'' to reduce,
refine, and replace animal use in testing when feasible. FDA
encourages sponsors to consult with FDA if they wish to use a non-
animal testing method they believe is suitable, adequate, validated,
and feasible. FDA will consider if such an alternative method could
be assessed for equivalency to an animal test method.
---------------------------------------------------------------------------

    FDA believes that the inclusion of important technical
characteristics and device performance parameters in the labeling will
also help mitigate use error and device malfunctions by informing end
users on device limitations. Therefore, FDA believes that the labeling
must identify key technical characteristics and performance parameters
of the surgical stapler and compatible staples needed for safe use of
the device. Key technical characteristics include stapler
specifications (e.g., jaw length, shaft length, jaw opening, and angles
of articulation), as well as compatible staple specifications (e.g.,
open and closed staple heights). Key technical characteristics also
include identification of any safety mechanisms of the stapler, such as
a color-firing zone and/or lock-out mechanism. Examples of key
performance parameters include information on firing the stapler, such
as the firing force, pre-fire compression time, and maximum number of
consecutive firings, and information relevant to creating a staple
line, such as the percentage of properly formed staples, number of
incremental firings required to complete a staple line, and maximum
number of reloads.
    FDA believes that the device must be demonstrated to be
biocompatible because the risk of adverse tissue reaction may result
from contact of the materials of the device with the body.
Additionally, because the risk of infection can arise from a
contaminated device, sterility testing must demonstrate the sterility
of the device. If any components of the device are reusable, the
labeling must include validated methods and instructions for cleaning
and sterilization of these reusable components. Validation of cleaning
and sterilization instructions must demonstrate that any reusable
device components can be safely and effectively reprocessed per the
recommended cleaning and sterilization protocol in the labeling.
    In addition, loss of package integrity can result in compromised
sterility and compromised device performance over time. Therefore,
shelf-life testing must demonstrate that the device maintains its
performance characteristics and the packaging of the device maintains
its integrity for the duration of the proposed shelf-life. Finally, the
labeling must also specify an expiration date to inform users of the
shelf-life of the device based on the shelf-life testing.
    Table 1 shows how FDA believes each risk to health described in
section V would be mitigated by the proposed special controls.

 Table 1--Risks to Health and Mitigation Measures for Surgical Staplers
                            for Internal Use
------------------------------------------------------------------------
       Identified risks to health              Mitigation measures
------------------------------------------------------------------------
Complications associated with device     Performance testing and
 failure/malfunction.                     Labeling.
Complications associated with use error/ Usability testing, Labeling
 improper device selection and use.       comprehension study, and
                                          Labeling.
Adverse Tissue Reaction................  Biocompatibility evaluation.

Infection..............................  Labeling, Sterility testing,
                                          and Shelf-Life testing.
------------------------------------------------------------------------

    If finalized, the reclassification of surgical staplers for
internal use into class II would subject these devices to premarket
notification under section 510(k) of the FD&C Act and part 807, subpart
E, and the identified special controls in this order. FDA believes that
the proposed reclassification would provide reasonable assurance of
safety and effectiveness of surgical staplers for internal use.

IX. Analysis of Environmental Impact

    The Agency has determined under 21 CFR 25.34(b) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.

X. Paperwork Reduction Act of 1995

    FDA tentatively concludes that this proposed order contains no new
collections of information. Therefore, clearance by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(PRA) (44 U.S.C. 3501-3520) is not required. This proposed order refers
to previously approved collections of information found in FDA
regulations. These collections of information are subject to review by
OMB under the PRA. The collections of information in part 807, subpart
E, have been approved under OMB control number 0910-0120; the
collections of information in 21 CFR part 814, subparts A through E,
have been approved under OMB control number 0910-0231; the collections
of information in 21 CFR part 801 have been approved under OMB control
number 0910-0485; and the collections of information in 21 CFR part 820
have been approved under OMB control number 0910-0073.

XI. Proposed Effective Date

    FDA proposes that any final order based on this proposed order
become effective on its date of publication in the Federal Register.
     Surgical staplers for internal use that have not been
offered for sale prior to the effective date of the final order or have
been offered for sale but are required to submit a new 510(k) under 21
CFR 807.81(a)(3): Manufacturers would have to obtain 510(k) clearance
before marketing their devices after the effective date of the order.
If a manufacturer markets such a device without receiving 510(k)
clearance, then FDA would consider taking action against such a
manufacturer under its usual enforcement policies.
     Surgical staplers for internal use that have been offered
for sale prior to the effective date of the final order and do not
already have 510(k) clearance: FDA does not intend to enforce
compliance with the 510(k) requirement or special controls until 180
days after the effective date of the final order. After that date, if a
manufacturer continues to market such a device but does not have 510(k)
clearance or FDA determines that the device is not substantially
equivalent or not compliant with special controls, then FDA would
consider taking action against such manufacturer under its usual
enforcement policies.
    For surgical staplers for internal use that have prior 510(k)
clearance, FDA would accept a new 510(k) and would issue a new
clearance letter, as appropriate, indicating substantial equivalence
and special controls compliance. These devices could serve as
predicates for new devices. These clearance letters would be made
publicly available in FDA's 510(k) database, and compliance with
special controls at the time of clearance would also be stated in the
publicly available 510(k) Summary posted in this database. FDA believes
that our public database is a transparent tool allowing users to
confirm that their devices have been submitted under a new 510(k) and
demonstrated conformance to applicable special controls.

XII. Codification of Orders

    Prior to the amendments by FDASIA, section 513(e) of the FD&C Act
provided for FDA to issue regulations to reclassify devices. Although
section 513(e) as amended requires FDA to issue final orders rather
than regulations, it also provides for FDA to revoke previously issued
regulations by order. FDA will continue to codify classifications and
reclassifications in the Code of Federal Regulations (CFR). Changes
resulting from final orders will appear in the CFR as changes to
codified classification determinations or as newly codified orders.
Therefore, under section 513(e)(1)(A)(i), as amended by FDASIA, in the
proposed order, we are proposing to revoke the classification of
surgical staplers in Sec.  878.4800 and to codify surgical staplers in
the new 21 CFR 878.4740, under which surgical staplers for internal use
would be reclassified into class II and surgical staplers for external
use would remain in class I.

XIII. References

    The following references are on display at the Dockets Management
Staff (see ADDRESSES) and are available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; references
with website addresses are also available electronically at https://www.regulations.gov. FDA has verified the website addresses, as of the
date this document publishes in the Federal Register, but websites are
subject to change over time.

1. FDA, ``Safe Use of Surgical Staplers and Staples--Letter to
Health Care Providers,'' March 8, 2019, available at https://www.fda.gov/MedicalDevices/Safety/LetterstoHealthCareProviders/ucm632938.htm.
2. Lipscomb, V., ``Surgical Staplers: Toy or Tool?'' In Practice.
2012; 34: 472-479.
3. Yim, A.P. and J.K. Ho, ``Malfunctioning of Vascular Staple Cutter
During Thoracoscopic Lobectomy.'' The Journal of Thoracic and
Cardiovascular Surgery. 1995;109(6):1252.
4. Angrisani, L., M. Lorenzo, V. Borrelli, et al., ``The Use of
Bovine Pericardial Strips on Linear Stapler to Reduce Extraluminal
Bleeding During Laparoscopic Gastric Bypass: Prospective Randomized
Clinical Trial.'' Obesity Surgery. 2004;14(9):1198-1202.
5. Champion, J.K. and M.D. Williams, ``Prospective Randomized
Comparison of Linear Staplers During Laparoscopic Roux-en-Y Gastric
Bypass.'' Obesity Surgery. 2003;13(6):855-859.
6. Nguyen, N.T., M. Longoria, S. Welbourne, et al., ``Glycolide
Copolymer Staple-Line Reinforcement Reduces Staple Site Bleeding
During Laparoscopic Gastric Bypass: A Prospective Randomized
Trial.'' Archives of Surgery. 2005;140(8):773-778.
7. Abu-Ghanem, Y., C. Meydan, L. Segev, et al., ``Gastric Wall
Thickness and the Choice of Linear Staples in Laparoscopic Sleeve
Gastrectomy: Challenging Conventional Concepts.'' Obesity Surgery.
2017;27(3):837-843.
8. Dresel, A., J.A. Kuhn, M.V. Westmoreland, et al., ``Establishing
a Laparoscopic Gastric Bypass Program.'' American Journal of
Surgery. 2002;184(6):617-620; discussion 620.

9. Jain, S., S.K. Jain, R. Kaza, et al., ``This Challenging
Procedure has Successful Outcomes: Laparoscopic Nephrectomy in
Inflammatory Renal Diseases.'' Urology Annals. 2018;10(1):35-40.
10. Kuthe, A., A. Haemmerle, K. Ludwig, et al., ``Multicenter
Prospective Evaluation of a New Articulating 5-mm Endoscopic Linear
Stapler.'' Surgical Endoscopy and Other Interventional Techniques.
2016;30(5):1883-1893.
11. Mattioli, G., M. Castagnetti, P. Repetto, et al.,
``Complications of Mechanical Suturing in Pediatric Patients.''
Journal of Pediatric Surgery. 2003;38(7):1051-1054.
12. Nadu, A., Y. Mor, J. Chen, et al., ``Laparoscopic Nephrectomy:
Initial Experience in Israel with 110 Cases.'' Israel Medical
Association Journal. 2005;7(7):431-434.
13. Pandya, S., J.J. Murray, J.A. Coller, et al., ``Laparoscopic
Colectomy: Indications for Conversion to Laparotomy.'' Archives of
Surgery. 1999;134(5):471-475.
14. Simper, S.C., J.M. Erzinger, and S.C. Smith, ``Comparison of
Laparoscopic Linear Staplers in Clinical Practice.'' Surgery for
Obesity and Related Diseases. 2007;3(4):446-450.
15. Allen, M.S., C. Deschamps, R.E. Lee, et al., ``Video-Assisted
Thoracoscopic Stapled Wedge Excision for Indeterminate Pulmonary
Nodules.'' Journal of Thoracic and Cardiovascular Surgery.
1993;106(6):1048-1052.
16. Asamura, H., K. Suzuki, H. Kondo, et al., ``Mechanical Vascular
Division in Lung Resection.'' European Journal of Cardio-Thoracic
Surgery: Official Journal of the European Association for Cardio-
thoracic Surgery. 2002;21(5):879-882.
17. Breda, A., J. Veale, J. Liao, et al., ``Complications of
Laparoscopic Living Donor Nephrectomy and Their Management: The UCLA
Experience.'' Urology. 2007;69(1):49-52.
18. Chan, D., J.T. Bishoff, L. Ratner, et al., ``Endovascular
Gastrointestinal Stapler Device Malfunction During Laparoscopic
Nephrectomy: Early Recognition and Management.'' Journal of Urology.
2000;164(2):319-321.
19. Cresswell, A.B., F.K.S. Welsh, T.G. John, et al., ``Evaluation
of Intrahepatic, Extra-Glissonian Stapling of the Right Porta
Hepatis vs. Classical Extrahepatic Dissection During Right
Hepatectomy.'' HPB. 2009;11(6):493-498.
20. Deng, D.Y., M.V. Meng, H.T. Nguyen, et al., ``Laparoscopic
Linear Cutting Stapler Failure.'' Urology. 2002;60(3):415-419.
21. Gonzalez Valverde, F.M., A.S. Cifuentes, M.R, Marin, et al.,
``Frequency and Causes of Conversion from Laparoscopic to Open Roux-
en-Y Gastric Bypass for Morbid Obesity: The Experience in Our
Service.'' Obesity Surgery. 2013;23(3):391-392.
22. Kaushik, M., A. Bagul, P.J. Yates, et al., ``Comparison of
Techniques of Vascular Control in Laparoscopic Donor Nephrectomy:
The Leicester Experience.'' Transplantation Proceedings.
2006;38(10):3406-3408.
23. Kim, C.B., K.W. Suh, J.I. Moon, et al., ``Roux-en-Y End-to-Side
Esophagojejunostomy with Stapler After Total Gastrectomy.'' Yonsei
Medical Journal. 1993;34(4):334-339.
24. Ky, A.J., T. Sonoda, and J.W. Milsom, ``One-Stage Laparoscopic
Restorative Proctocolectomy: An Alternative to the Conventional
Approach?'' Diseases of the Colon and Rectum. 2002;45(2):207-211.
25. Kyzer, S. and P.H. Gordon, ``Experience with the Use of the
Circular Stapler in Rectal Surgery.'' Diseases of the Colon and
Rectum. 1992;35(7):696-706.
26. Liu, K.L., Y.J. Chiang, H.H. Wang, et al., ``Techniques of
Vascular Control in Laparoscopic Donor Nephrectomy.''
Transplantation Proceedings. 2008;40(7):2342-2344.
27. Offodile, A.C. II, D.L. Feingold, A. Nasar, et al., ``High
Incidence of Technical Errors Involving the EEA Circular Stapler: A
Single Institution Experience.'' Journal of the American College of
Surgeons. 2010;210(3):331-335.
28. Raoof, M., T.A. Aloia, J.N. Vauthey, et al., ``Morbidity and
Mortality in 1,174 Patients Undergoing Hepatic Parenchymal
Transection Using a Stapler Device.'' Annals of Surgical Oncology.
2014;21(3):995-1001.
29. Rosenblatt, G.S. and M.J. Conlin, ``Clipless Management of the
Renal Vein During Hand-Assist Laparoscopic Donor Nephrectomy.'' BMC
Urology. 2006;6.
30. Seshadri, R.A., S.K. Thammaiah, and V. Vaidhyalingam, ``Modified
Technique of Stapled Esophagojejunostomy Without a Purse-String
Suture.'' Indian Journal of Surgical Oncology. 2011;2(3):189-192.
31. Szwerc, M.F., R.J. Landreneau, R.S. Santos, et al.,
``Minithoracotomy Combined with Mechanically Stapled Bronchial and
Vascular Ligation for Anatomical Lung Resection.'' Annals of
Thoracic Surgery. 2004;77(6):1904-1910.
32. Zhang, B., J. Ma, X. Yan, et al., ``Left Minimally Invasive
Esophagectomy in a Patient with Synchronous Esophageal and Lung
Cancers: Case Report.'' Medicine (Baltimore). 2018;97(2).
33. Folkesson, J., J. Nilsson, L. Pahlman, et al., ``The Circular
Stapling Device as a Risk Factor for Anastomotic Leakage.''
Colorectal Disease. 2004 Jul; 6(4):275-9.
34. Ouchi, A., A. Masahiko, K. Aono, et al., ``Staple-line
Recurrence Arising 10 Years After Functional End-to-End Anastomosis
for Colon Cancer: A Case Report.'' Surgical Case Reports. 2015 Dec;
1:7.
35. Hsu, T.C. and M.J. Chen, ``Presence of Colon Carcinoma Cells at
the Resection Line May Cause Recurrence Following Stapling
Anastomosis.'' Asian Journal of Surgery. 2018 Nov; 41(6):569-572.
36. Checkan, E. and R.L. Whelan, ``Surgical Stapling Device-Tissue
Interactions: What Surgeons Need to Know to Improve Patient
Outcomes.'' Medical Devices [Auckland, NZ]. 2014(7):305-318.
37. Betzold, R. and J.A. Laryea, ``Staple Line/Anastomotic
Reinforcement and Other Adjuncts: Do They Make a Difference?''
Clinics in Colon and Rectal Surgery. 2014 Dec; 27(4): 156-161.
38. Brown, S.L. and E.K. Woo, ``Surgical Stapler-Associated
Fatalities and Adverse Events Reported to the Food and Drug
Administration.'' Journal of the American College of Surgeons.
2004;199(3):374-380.
39. Swayze, S. and S. Rich, ``Promoting Safe Use of Medical
Devices.'' The Online Journal of Issues in Nursing. 2011;17(1):9.

List of Subjects in 21 CFR Part 878

    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 878 be amended as follows:

PART 878--GENERAL AND PLASTIC SURGERY DEVICES

0
1. The authority citation for part 878 continues to read as follows:

    Authority: 21 U.S.C. 351, 360, 360c, 360e, 360j, 360l, 371.

0
2. Add Sec.  878.4740 to subpart E to read as follows:

Sec.  878.4740  Surgical stapler.

    (a) Surgical stapler for external use. (1) Identification. A
surgical stapler for external use is a specialized prescription device
used to deliver compatible staples to skin during surgery.
    (2) Classification. Class I (general controls). The device is
exempt from the premarket notification procedures in subpart E of part
807 of this chapter, subject to the limitations in Sec.  878.9.
    (b) Surgical stapler for internal use. (1) Identification. A
surgical stapler for internal use is a specialized prescription device
used to deliver compatible staples to internal tissues during surgery
for resection, transection, and creating anastomoses.
    (2) Classification. Class II (special controls). The special
controls for this device are:
    (i) Performance testing must demonstrate that the stapler, when
used with compatible staples, performs as intended under anticipated
conditions of use. Performance testing must include the following:
    (A) Evaluation of staple formation characteristics in the maximum
and minimum tissue thicknesses for each staple type;
    (B) Measurement of the worst-case deployment pressures on stapler
firing force;
    (C) Measurement of staple line strength;
    (D) Confirmation of staple line integrity; and
    (E) In vivo confirmation of staple line hemostasis.

    (ii) Usability testing and a labeling comprehension study must
demonstrate that the clinician can correctly select and use the device,
as identified in the labeling, based on reading the directions for use.
    (iii) The elements of the device that may contact the patient must
be demonstrated to be biocompatible.
    (iv) Performance data must demonstrate the sterility of the device.
    (v) Validation of cleaning and sterilization instructions must
demonstrate that any reusable device components can be safely and
effectively reprocessed per the recommended cleaning and sterilization
protocol in the labeling.
    (vi) Performance data must support the shelf life of the device by
demonstrating continued device functionality, sterility, and package
integrity over the identified shelf life.
    (vii) Labeling of the device must include the following:
    (A) Unless data demonstrates the safety of doing so,
contraindications must be identified regarding use of the device on
tissues for which the risk of stapling outweighs any reasonably
foreseeable benefit due to known complications, including the stapling
of necrotic or ischemic tissues and tissues outside of the labeled
limits of tissue thickness.
    (B) Unless available information demonstrates that the specific
warnings do not apply, the labeling must provide appropriate warnings
regarding how to avoid known hazards associated with device use
including:
    (i) Avoidance of obstructions to the creation of the staple line
and the unintended stapling of other anatomic structures;
    (ii) Avoidance of clamping and unclamping of delicate tissue
structures to prevent tissue damage;
    (iii) Avoidance of use of the stapler on large blood vessels, such
as the aorta;
    (iv) Establishing and maintaining proximal control of blood vessels
prior to stapling;
    (v) Appropriate measures to take if a stapler malfunction occurs
while applying staples across a blood vessel, such as clamping or
ligating the vessel before releasing the stapler, while the stapler is
still closed on the tissue; and
    (vi) Ensuring stapler compatibility with staples.
    (C) Specific user instructions for proper device use including
measures associated with the prevention of device malfunction,
evaluation of the appropriateness of the target tissue for stapling,
and evaluation of the resultant staple line.
    (D) List of staples with which the stapler has been demonstrated to
be compatible.
    (E) Identification of key performance parameters and technical
characteristics of the stapler and the compatible staples needed for
safe use of the device.
    (F) Information regarding tissues on which the stapler is intended
to be used.
    (G) Identification of safety mechanisms of the stapler.
    (H) Validated methods and instructions for reprocessing of any
reusable device components.
    (I) An expiration date/shelf life.
    (viii) Package labels must include critical information and
technical characteristics necessary for proper device selection.
0
3. In Sec.  878.4800, revise paragraph (a) to read as follows:

Sec.  878.4800  Manual surgical instrument for general use.

    (a) Identification. A manual surgical instrument for general use is
a nonpowered, hand-held, or hand-manipulated device, either reusable or
disposable, intended to be used in various general surgical procedures.
The device includes the applicator, clip applier, biopsy brush, manual
dermabrasion brush, scrub brush, cannula, ligature carrier, chisel,
clamp, contractor, curette, cutter, dissector, elevator, skin graft
expander, file, forceps, gouge, instrument guide, needle guide, hammer,
hemostat, amputation hook, ligature passing and knot-tying instrument,
knife, blood lancet, mallet, disposable or reusable aspiration and
injection needle, disposable or reusable suturing needle, osteotome,
pliers, rasp, retainer, retractor, saw, scalpel blade, scalpel handle,
one-piece scalpel, snare, spatula, disposable or reusable stripper,
stylet, suturing apparatus for the stomach and intestine, measuring
tape, and calipers. A surgical instrument that has specialized uses in
a specific medical specialty is classified in separate regulations in
parts 868 through 892 of this chapter.
* * * * *

    Dated: April 18, 2019.
Lowell J. Schiller,
Principal Associate Commissioner for Policy.
[FR Doc. 2019-08260 Filed 4-23-19; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 85, Number 205 (Thursday, October 22, 2020)]
[Notices]
[Pages 67355-67357]
[FR Doc No: 2020-23393]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-1806]

Fit for Use Pilot Program Invitation for the Clinical Data
Interchange Standards Consortium for Standard for Exchange of
Nonclinical Data Implementation Guide Developmental and Reproductive
Toxicology: Version 1.1

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
that it intends to conduct a Fit for Use (FFU) pilot program to test
the processing and analysis of nonclinical study data provided
electronically for the Clinical Data Interchange Standards Consortium
(CDISC) for Standard for Exchange of Nonclinical Data (SEND)
Implementation Guide (IG): Developmental and Reproductive Toxicology
v1.1 (SEND-DART). The Agency's Center for Drug Evaluation and Research
(CDER) will test the processing and analysis of nonclinical study data
provided electronically in SEND-DART format. FDA is inviting individual
firms that wish to participate in this pilot program to submit
participation requests via email or in writing.

DATES: To be considered for participation in the pilot program, submit
electronic or written requests by February 26, 2021. See the ADDRESSES
section for participation request instructions.

ADDRESSES: Submit electronic requests to participate in the pilot and
comments regarding this pilot project to Docket No. FDA-2020-N-1806 at
https://www.regulations.gov. Submit written requests to participate in
the pilot and comments regarding the pilot to Dockets Management Staff
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852. The https://www.regulations.gov electronic filing
system will accept comments until 11:59 p.m. Eastern Time by February
26, 2021. Comments received by mail/hand delivery/courier (for written/
paper submissions) will be considered timely if they are postmarked or
the delivery service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2020-N-1806 for ``Fit for Use Pilot Program Invitation for the
Clinical Data Interchange Standards Consortium for Standard for
Exchange of Nonclinical Data Implementation Guide: Developmental and
Reproductive Toxicology v1.1.'' Received comments will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://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 Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Jesse Anderson, Office of
Computational Science, Center for Drug Evaluation and Research, Food
and Drug Administration, 10903 New Hampshire Ave., Bldg. 21, Rm. 1553,
Silver Spring, MD 20993-0002,<PHONE_NUMBER><EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. Background

    Data Standards help FDA receive, process, review and archive
submission data more efficiently and effectively. Study data standards
describe a standard way to exchange clinical and nonclinical research
data between computer systems. These standards provide a consistent
general framework for organizing study data, including templates for
datasets, standard names for variables, and a standard way of doing
calculations with common variables. Study data standards are required
for study data submitted to FDA's CDER per the published guidance.\1\
---------------------------------------------------------------------------

    \1\ See the guidance ``Providing Regulatory Submissions in
Electronic Format-Standardized Study Data; Guidance for Industry''
at https://www.fda.gov/media/82716/download.
---------------------------------------------------------------------------

    CDISC is an open, multidisciplinary, nonprofit organization that
has established worldwide industry standards to support the electronic
acquisition and submission of study data and metadata for medical and
biopharmaceutical product development.\2\ CDISC is currently
facilitating and testing the extension of the SEND-DART standard for
nonclinical toxicology data.
---------------------------------------------------------------------------

    \2\ See the CDISC website at https://www.cdisc.org.
---------------------------------------------------------------------------

    CDER completed a pilot project evaluating SEND 3.1 using SEND-
formatted sample toxicology datasets. Phase 1 of the pilot supported
the development of a SEND Implementation Guide (SENDIG) describing the
process for formatting data from single and repeat-dose animal toxicity
and carcinogenicity studies for submission purposes. During Phase 2 of
the pilot, CDER evaluated submission of SEND formatted datasets and
evaluated data validation and analysis tools capabilities. The outcomes
of this pilot resulted in improvements to the SENDIG 3.1.\3\
---------------------------------------------------------------------------

    \3\ The updated guide can be found at https://www.cdisc.org. FDA
has verified the website address, but the Agency is not responsible
for any subsequent changes to the website address after this
document publishes in the Federal Register.
---------------------------------------------------------------------------

    Based on published guidance \4\ studies initiated after December
17, 2016, must be submitted with data formatted in accordance with the
data standards listed in the FDA Data Standards Catalog for new drug
applications (NDAs), biologics license applications (BLAs), and
abbreviated new drug applications (ANDAs). For investigational new drug
applications (INDs), the requirement \5\ applies to studies initiated
after December 17, 2017. Different versions of SENDIGs are on the Data
Standards Catalog, and the submission of SEND nonclinical datasets is
expected to continue to increase in the future. This pilot will
evaluate the compliance of sample SEND-DART datasets submitted to CDER.
As part of this evaluation and in anticipation of FDA receiving
datasets for regulatory review, the CDISC SEND team, in collaboration
with CDER and available pilot participants, will update the SENDIG-DART
as needed to include specific data elements and terms.
---------------------------------------------------------------------------

    \4\ See the Technical Rejection Criteria for Study Data at
https://www.fda.gov/media/100743/download.
    \5\ See footnote 4.

---------------------------------------------------------------------------

II. Project Participation

    CDER is seeking a maximum of five participants in this pilot. The
Center will use its discretion in choosing participants based on the
completeness of the submission per the guidelines below. CDER requests
participants to submit a nonclinical study package containing the
materials:
     SEND-DART v1.1 datasets;
     final related study report containing individual animal
data and summary tables \6\ (PDF Format);
---------------------------------------------------------------------------

    \6\ See the FDA Study Data Resources web page, available at
https://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm.
---------------------------------------------------------------------------

     nonclinical Study Data Reviewers Guide; \7\
---------------------------------------------------------------------------

    \7\ See the PhUSE Wiki web page, available at https://www.phusewiki.org/wiki/index.php?title=Nonclinical_Study_Data_Reviewers_Guide.
---------------------------------------------------------------------------

     define.xml (v2.0); \8\ and
---------------------------------------------------------------------------

    \8\ See Footnote 6.
---------------------------------------------------------------------------

     sample standardization study protocol.
    CDER will prioritize nonclinical packages that contain Embryo-Fetal
Development (EFD) Toxicity studies (using pre-bred females only) that
contain data that is consistent with SEND-DART v1.1. Therefore, the
studies that meet as many of the following use cases as possible will
be the most sought out as participants in this pilot:
     Small animals (rodents, rabbits), pre-bred females,
treatment period during implanted embryo's major organogenesis period;
     material toxicity endpoints (minimum CL, BW, FW, DS);
     caesarean section endpoints in PY, IC, FM, FX (pregnancy,
Corpora Lutea, implantations, resorptions, fetal viability, fetal sex
and body weights, fetal morphology);
     toxicokinetic females to illustrate in Trial Design and
pregnancy results (PC, PP domains optional);
     LB domain optional since not routine in EFD Toxicity
study;
     MA optional (if gross observations scheduled, may not be
in preliminary EFD study);
     gravid uterine weights (OM domain) for deriving gravid
uterus adjusted body weight; and
     pregnant, non-pregnant, toxicokinetic females to
illustrate in Trial Design and pregnancy results (PC, PP domains
optional).
    Please indicate in your request for participation the extent to
which your submission will meet the above listed criteria. Please also
indicate whether you are willing to share anonymized data with the
CDISC FFU team.
    This pilot is intended to inform of the readiness of the SEND-DART
standard and support improvements to the SEND-DART that will benefit
FDA and submitters. Pilot participants commit to publicly share lessons
learned with the CDISC SEND team to ensure that the CDISC SEND standard
is improved for the community. Participants may redact any sensitive
information as needed to enable sharing FDA feedback with the CDISC
SEND team.

III. Requests for Participation

    Requests to participate in the SEND-DART FFU pilot are to be
identified with the Docket No. FDA-2020-N-1806. Interested persons
should include the following information in the request: Contact name,
contact phone number, email address, name of the sponsor, and address,
as well as the description of the criteria met, addressing each of the
items in the Project participation section.
    Once requests for participation are received CDER will contact
interested sponsors to discuss the pilot project and clarify
requirements and expectations. The elapsed time duration of the pilot
is expected to be approximately 9 months but may be extended as needed.

    Dated: October 16, 2020.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2020-23393 Filed 10-21-20; 8:45 am]
BILLING CODE 4164-01-P


[Federal Register Volume 86, Number 118 (Wednesday, June 23, 2021)]
[Notices]
[Pages 32921-32922]
[FR Doc No: 2021-13175]

-----------------------------------------------------------------------

ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPP-2021-0132; FRL-10025-30]

Product Cancellation Order for Certain Pesticide Registrations;
Correction

AGENCY: Environmental Protection Agency (EPA).

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: EPA issued a notice in the Federal Register of June 8, 2021,
concerning cryolite product cancellations voluntarily requested by the
registrants and accepted by the Agency. This notice is being issued to
correct Table 1 of the cancellation order by removing five entries that
indicated an incorrect cancellation date and correcting the
cancellation date and the corresponding existing stocks provision date
in Units IV and VI for the affected products.

FOR FURTHER INFORMATION CONTACT: Alexander Hazlehurst, Pesticide
Reevaluation Division (7508P), Office of Pesticide Programs,
Environmental Protection Agency, 1200 Pennsylvania Ave. NW, Washington,
DC 20460-0001; telephone number:<PHONE_NUMBER> email address:
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION:

I. General Information

A. Does this action apply to me?

    This action is directed to the public in general, and may be of
interest to a wide range of stakeholders including environmental, human
health, and agricultural advocates; the chemical industry; pesticide
users; and members of the public interested in the sale, distribution,
or use of pesticides. Since others also may be interested, the Agency
has not attempted to describe all the specific entities that may be
affected by this action.

B. How can I get copies of this document and other related information?

    The docket for this action, identified by docket identification
(ID) number

EPA-HQ-OPP-2021-0132, is available at http://www.regulations.gov or at
the Office of Pesticide Programs Regulatory Public Docket (OPP Docket)
in the Environmental Protection Agency Docket Center (EPA/DC), West
William Jefferson Clinton Bldg., Rm. 3334, 1301 Constitution Ave. NW,
Washington, DC 20460-0001. 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<PHONE_NUMBER>, and the
telephone number for the OPP Docket is<PHONE_NUMBER>. Due to the
public health concerns related to COVID-19, the EPA Docket Center (EPA/
DC) and Reading Room is closed to visitors with limited exceptions. The
staff continues to provide remote customer service via email, phone,
and webform. For the latest status information on EPA/DC services and
docket access, visit https://www.epa.gov/dockets.

II. What does this correction do?

    This notice is being issued to correct Table 1 in Unit II and the
corresponding existing stocks and provisions dates in Units IV and VI
of the cancellation notice that published in the Federal Register on
June 8, 2021 (86 FR 30460) (FRL-10024). As such, FR Doc. 2021-11919
that published in the Federal Register on June 8, 2021 (86 FR 30460)
(FRL-10024-48) is corrected as follows:
    1. On page 30460, in Table 1, remove the complete entries for
``10163-41, 10163-225, 10163-242, 10163-243, and FL000011.''
    2. Insert the following table below Table 1.

                     Table 1A--Product Cancellations
------------------------------------------------------------------------
      EPA Registration No.           Product name     Active ingredients
------------------------------------------------------------------------
10163-41........................  Prokil Cryolite 96  Cryolite.
10163-225.......................  Gowan Cryolite      Cryolite.
                                   Bait.
10163-242.......................  Prokil Cryolite 75- Cryolite.
                                   Dust.
10163-243.......................  Prokil Cryolite 50- Cryolite.
                                   Dust.
FL000011........................  Prokil Cryolite 96  Cryolite.
------------------------------------------------------------------------

    3. On page 30461, in Unit IV., insert ``The effective date of the
cancellations that are the subject of this notice for the product
registrations identified in Table 1A of Unit II., will be September 30,
2022.''
    4. On page 30461, in Unit VI., insert ``The registrant may continue
to sell and distribute existing stocks of the cryolite products listed
in Table 1A of Unit II. until March 31, 2024, which is 18 months after
the effective date of the cancellations.''
    Prior to the issuance of the cancellation order, the registrant of
the five cryolite product registrations in Table 1A, requested the
cancellations to be effective on September 30, 2022. The Agency
intended to accept this effective cancellation date, but inadvertently
neglected to separate out these products with the correct effective
date in the prior cancellation order. In addition, as requested, the
registrant may continue to sell and distribute existing stocks of the
cryolite products listed in Table 1A of Unit II. until March 31, 2024,
which is 18 months after the effective date of the cancellations.
Persons other than the registrants may sell, distribute, or use
existing stocks of products listed in Table 1A of Unit II. until
exhausted, provided that such sale, distribution, or use is consistent
with the terms of the previously approved labeling on, or that
accompanied, the canceled products.

    Authority: 7 U.S.C. 136 et seq.

    Dated: June 16, 2021.
Mary Reaves,
Director, Pesticide Re-Evaluation Division, Office of Pesticide
Programs.
[FR Doc. 2021-13175 Filed 6-22-21; 8:45 am]
BILLING CODE 6560-50-P