[Federal Register Volume 60, Number 31 (Wednesday, February 15, 1995)]
[Proposed Rules]
[Pages 8595-8609]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-3805]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 876
[Docket No. 94N-0380]
Gastroenterology-Urology Devices; Effective Date of the
Requirement for Premarket Approval of the Implanted Mechanical/
Hydraulic Urinary Continence Device
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule; opportunity to request a change in
classification.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to require
the filing of a premarket approval application (PMA) or a notice
[[Page 8596]] of completion of a product development protocol (PDP) for
the implanted mechanical/hydraulic urinary continence device, a medical
device. The agency is also summarizing its proposed findings regarding
the degree of risk of illness or injury designed to be eliminated or
reduced by requiring the device to meet the statute's approval
requirements, and the benefits to the public from the use of the
device. In addition, FDA is announcing an opportunity for interested
persons to request that the agency change the classification of the
device based on new information.
DATES: Written comments by June 15, 1995; requests for a change in
classification by March 2, 1995. FDA intends that, if a final rule
based on this proposed rule is issued, PMA's will be required to be
submitted within 90 days of the effective date of the final rule.
ADDRESSES: Submit written comments or requests for a change in
classification to the Dockets Management Branch (HFA-305), Food and
Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.
FOR FURTHER INFORMATION CONTACT: John H. Baxley, or John F. Guest,
Center for Devices and Radiological Health (HFZ-470), Food and Drug
Administration, 9200 Corporate Blvd., Rockville, MD 20850, 301-594-
2194.
SUPPLEMENTARY INFORMATION:
I. Background
Section 513 of the Federal Food, Drug, and Cosmetic Act (the act)
(21 U.S.C. 360c) requires the classification of medical devices into
one of three regulatory classes: Class I (general controls), class II
(special controls), and class III (premarket approval). Generally,
devices that were on the market before May 28, 1976, the date of
enactment of the Medical Device Amendments of 1976 (the amendments)
(Pub. L. 94-295), and devices marketed on or after that date that are
substantially equivalent to such devices, have been classified by FDA.
For the sake of convenience, this preamble refers to both the devices
that were on the market before May 28, 1976, and the substantially
equivalent devices that were marketed on or after that date as
``preamendments devices.''
Section 515(b)(1) of the act (21 U.S.C. 360e(b)(1)) establishes the
requirement that a preamendments device that FDA has classified into
class III is subject to premarket approval. A preamendments class III
device may be commercially distributed without an approved PMA or
declared completed PDP until 90 days after FDA's promulgation of a
final rule requiring premarket approval for the device, or 30 months
after final classification of the device under section 513 of the act,
whichever is later. Also, a preamendments device subject to the
rulemaking procedures under section 515(b) of the act is not required
to have an approved investigational device exemption (IDE) (part 812
(21 CFR part 812)) contemporaneous with its interstate distribution
until the date identified by FDA in the final rule requiring the
submission of a PMA for the device.
Section 515(b)(2)(A) of the act provides that a proceeding to
promulgate a final rule to require premarket approval shall be
initiated by publication, in the Federal Register, of a notice of
proposed rulemaking containing: (1) The proposed rule; (2) proposed
findings with respect to the degree of risk of illness or injury
designed to be eliminated or reduced by requiring the device to have an
approved PMA or declared completed PDP and the benefit to the public
from the use of the device; (3) an opportunity for the submission of
comments on the proposed rule and the proposed findings; and (4) an
opportunity to request a change in the classification of the device
based on new information relevant to the classification of the device.
Section 515(b)(2)(B) of the act provides that if FDA receives a
request for a change in the classification of the device within 15 days
of the publication of the notice, FDA shall, within 60 days of the
publication of the notice, consult with the appropriate FDA advisory
committee and publish a notice denying the request for change of
classification or announcing its intent to initiate a proceeding to
reclassify the device under section 513(e) of the act. If FDA does not
initiate such a proceeding, section 515(b)(3) of the act provides that
FDA shall, after the close of the comment period on the proposed rule
and consideration of any comments received, promulgate a final rule to
require premarket approval, or publish a notice terminating the
proceeding. If FDA terminates the proceeding, FDA is required to
initiate reclassification of the device under section 513(e) of the
act, unless the reason for termination is that the device is a banned
device under section 516 of the act (21 U.S.C. 360f).
If a proposed rule to require premarket approval for a
preamendments device is made final, section 501(f)(2)(B) of the act (21
U.S.C. 351(f)(2)(B)) requires that a PMA or notice of completion of a
PDP for any such device be filed within 90 days of the date of
promulgation of the final rule or 30 months after final classification
of the device under section 513 of the act, whichever is later. If a
PMA or notice of completion of a PDP is not filed by the later of the
two dates, commercial distribution of the device is required to cease.
The device may, however, be distributed for investigational use if the
manufacturer, importer, or other sponsor of the device complies with
the IDE regulations. If a PMA or notice of completion of a PDP is not
filed by the later of the two dates, and no IDE is in effect, the
device is deemed to be adulterated within the meaning of section
501(f)(1)(A) of the act, and subject to seizure and condemnation under
section 304 of the act (21 U.S.C. 334) if its distribution continues.
Shipment of the device in interstate commerce will be subject to
injunction under section 302 of the act (21 U.S.C. 332), and the
individuals responsible for such shipment will be subject to
prosecution under section 303 of the act (21 U.S.C. 333). FDA has in
the past requested that manufacturers take action to prevent the
further use of devices for which no PMA or notice of completion of a
PDP has been filed and may determine that such a request is appropriate
for implanted mechanical/hydraulic urinary continence devices.
The act does not permit an extension of the 90-day period after
promulgation of a final rule within which an application or a notice is
required to be filed. The House Report on the amendments states that
``the thirty month `grace period' afforded after classification of a
device into class III * * * is sufficient time for manufacturers and
importers to develop the data and conduct the investigations necessary
to support an application for premarket approval.'' (H. Rept. 94-853,
94th Cong., 2d sess. 42 (1976).)
A. Classification of the Implanted Mechanical Hydraulic Urinary
Continence Device
In the Federal Register of November 23, 1983 (48 FR 53012 at
53026), FDA issued a final rule classifying the implanted mechanical/
hydraulic urinary continence device into class III Sec. 876.5280 (21
CFR 876.5280). The preamble to the proposal to classify the device (46
FR 7610, January 23, 1981) included the recommendation of the
Gastroenterology-Urology Devices Advisory Panel (the Panel), an FDA
advisory committee, which met on September 26 and 27, 1976, regarding
the classification of the device. The Panel recommended that the device
be in class III, and identified certain risks to health presented by
the device. FDA agreed with the Panel's [[Page 8597]] recommendation
and proposed that the implanted mechanical/hydraulic urinary continence
device be classified into class III. The proposal stated that the
agency believed that general controls and performance standards are
insufficient to provide reasonable assurances of the safety and
effectiveness of the device and that there is insufficient information
to establish a standard to provide reasonable assurances of the safety
and effectiveness of the device. The proposal stated that premarket
approval is necessary for this device because it presents a potential
unreasonable risk of injury due to: (1) Adverse tissue reaction and
erosion; (2) leakage of urine secondary to device defects; (3)
infection resulting from defects in the design, construction,
packaging, or processing of the device; (4) urinary tract infection,
secondary to urine stasis, occurring as a result of the inflation cuff
locking in the closed position; and (5) additional surgery that might
be required as a result of a malfunction of the device. In support of
its proposal to strengthen regulatory surveillance of the device, FDA
cited references supporting the proposed classification.
The preamble to the November 23, 1983, final rule (48 FR 53012)
classifying the device into class III advised that the earliest date by
which PMA's for the device could be required was June 30, 1986, or 90
days after promulgation of a rule requiring premarket approval for the
device, whichever occurs later. In the Federal Register of January 6,
1989 (54 FR 550), FDA published a notice of intent to initiate
proceedings to require premarket approval of 31 preamendments class III
devices assigned a high priority by FDA for the application of
premarket approval requirements. Among other things, the notice
described the factors FDA takes into account in establishing priorities
for proceedings under section 515(b) of the act for promulgating final
rules requiring that preamendments class III devices have approved
PMA's. Although the implanted mechanical/hydraulic urinary continence
device was not listed among these 31 devices, the agency has received
more than 2,700 medical device reports (MDR's) since 1984 for this
device. Additionally, the types of problems identified in these reports
are similar to those identified during the classification proceedings
of the device. Therefore, FDA has determined that the implanted
mechanical/hydraulic urinary continence device identified in
Sec. 876.5280 has a high priority for initiating a proceeding to
require premarket approval. Accordingly, FDA is commencing a proceeding
under section 515(b) of the act to require that the implanted
mechanical/hydraulic urinary continence device has an approved PMA or a
declared completed PDP.
B. Dates New Requirements Apply
In accordance with section 515(b) of the act, FDA is proposing to
require that a PMA or a notice of completion of a PDP be filed with the
agency for the implanted mechanical/hydraulic urinary continence device
within 90 days after promulgation of any final rule based on this
proposal. An applicant whose device was legally in commercial
distribution before May 28, 1976, or has been found by FDA to be
substantially equivalent to such a device, will be permitted to
continue marketing the implanted mechanical/hydraulic urinary
continence device during FDA's review of the PMA or notice of
completion of the PDP. FDA intends to complete the review of any PMA
for the device within 180 days and a notice of completion of a PDP
within 90 days of the date of filing. FDA cautions that, under section
515(d)(1)(B)(i) of the act, FDA may not enter into an agreement to
extend the review period for a PMA beyond 180 days unless the agency
finds that ``* * * the continued availability of the device is
necessary for the public health.''
FDA intends that, under Sec. 812.2(d), the preamble to any final
rule based on this proposal will state that, as of the date on which a
PMA or notice of completion of a PDP is required to be filed, the
exemptions in Sec. 812.2(c)(1) and (c)(2) from the requirements of the
IDE regulations for preamendments class III devices will cease to apply
to any implanted mechanical/hydraulic urinary continence device which
is: (1) Not legally on the market on or before that date, or (2)
legally on the market on or before that date but for which a PMA is not
filed by that date, or for which PMA approval has been denied or
withdrawn.
If a PMA or notice of completion of a PDP for the implanted
mechanical/hydraulic urinary continence device is not filed with FDA
within 90 days after the date of promulgation of any final rule
requiring premarket approval for the device, commercial distribution of
the device must cease. The device may be distributed for
investigational use only if the requirements of the IDE regulations
regarding significant risk devices are met. The requirements for
significant risk devices include submitting an IDE application to FDA
for its review and approval. An approved IDE is required to be in
effect before an investigation of the device may be initiated or
continued. FDA, therefore, cautions that IDE applications should be
submitted to FDA at least 30 days before the end of the 90-day period
after the final rule to avoid interrupting investigations.
C. Description of the Device
An implanted mechanical/hydraulic urinary continence device is a
device used to treat urinary incontinence by the application of
continuous or intermittent pressure to occlude the urethra. The totally
implanted device may consist of either a static pressure pad, or a
system with a container of saline or radiopaque fluid in the abdomen
and a manual pump and valve under the skin surface that is connected by
tubing to an adjustable pressure pad or to a cuff around the urethra.
The fluid is pumped as needed from the container to inflate the pad or
cuff to compress the urethra. These devices are most commonly
constructed from silicone elastomers. Additionally, static pressure pad
designs have been known to contain silicone gel and/or polyurethane
foam covering.
The proposed rule to require premarket approval of implanted
mechanical/hydraulic urinary continence devices applies to legally
marketed implanted mechanical/hydraulic urinary continence devices
identified above that were commercially distributed before May 28,
1976, and to devices introduced into commercial distribution since that
date that have been found to be substantially equivalent to such
implanted mechanical/hydraulic urinary continence devices.
D. Proposed Findings With Respect to Risks and Benefits
As required by section 515(b) of the act, FDA is publishing its
proposed findings regarding: (1) The degree of risk of illness or
injury designed to be eliminated or reduced by requiring the implanted
mechanical/hydraulic urinary continence device to have an approved PMA
or a declared completed PDP; and (2) the benefits to the public from
the use of the device.
E. Degree of Risk
After considering the information discussed by the Panel during the
classification proceedings, as well as the published literature and
MDR's, FDA has evaluated the risks associated with the implanted
mechanical/hydraulic urinary continence device. FDA now believes that
the following are [[Page 8598]] significant risks associated with the
use of the implanted mechanical/hydraulic urinary continence device:
1. Erosion of the Implanted Mechanical/Hydraulic Urinary Continence
Device
Erosion is the destruction or breakdown of tissue and is the most
common cause of failure in the implanted mechanical/hydraulic urinary
continence device (Refs. 1 through 5). Cuff erosion into the urethra or
bladder neck is a serious complication that has been frequently
reported (Refs. 3 and 6 through 15). This type of erosion makes
reimplantation difficult and is associated with higher complication
rates for reimplantation (Refs. 1 and 16 through 18) of the device.
Erosion of the pump through the labia, vagina, scrotum (Refs. 14 and 19
through 21), and the perineum (Refs. 2, 9, and 22) have also been
reported.
Erosion often occurs as a result of low grade, nonclinical
infection of the prosthesis (Refs. 9, 14, and 23 through 28). Other
factors which can contribute to erosion include previous surgery (Ref.
11), poor vascularization (Refs. 27 and 29 through 31), prior pelvic
irradiation (Refs. 17, 28, and 32 through 35), improper cuff size (Ref.
30), improper reservoir volume (Ref. 17), surgical injury (Refs. 18 and
24), excessive urethral compression (Ref. 16), and premature activation
(Refs. 19 and 27).
2. Infection
Infection, a risk of any surgical implant procedure, is associated
with the use of implanted mechanical/hydraulic urinary continence
devices (Refs. 7, 10, 12, 33, and 36 through 39). Infection is one of
the most serious potential complications of device implantation and
usually necessitates removal of the prosthesis (Refs. 7, 40, and 41).
As in any implantation procedure, compromised device sterility and/or
surgical techniques may be major contributing factors to this risk
(Refs. 40 and 42). Additionally, a life-long risk for hematogenously
seeded infection possibly exists in these patients and antibacterial
prophylaxis for subsequent dental and surgical procedures may be needed
(Ref. 40).
3. Mechanical Malfunctions
Fluid leakage is one of the most commonly reported mechanical
malfunctions (Refs. 2, 26, 28, 37, 43, and 44) of implanted mechanical/
hydraulic urinary continence devices. Fluid can leak from the cuff or
pad (Refs. 7, 13, 21, 31, and 45), reservoir (Refs. 7, 13, and 31), or
connectors (Ref. 10). Leakage from the cuff has been associated with
cuff folding and attendant material wear (Refs. 31, 36, and 46). This
malfunction results in inadequate cuff pressure and incontinence (Ref.
7). Tube kinking is another reported device malfunction (Refs. 7, 12,
26, 28, 34, 37, 43, 44, and 47). Also, disconnection of the tubing from
components of the device can occur (Ref. 19). Pump assembly failure is
another noted complication (Refs. 2, 19, 36, 37, and 44) of this
implant. This can include malfunction of the valves within the
hydraulic system (Ref. 45). Finally, balloon herniation has been noted
(Ref. 17). Device malfunction usually requires replacement or revision
surgery (Refs. 7 and 43).
4. Iatrogenic Disorders
Iatrogenic complications can occur as a result of any medical
procedure, including implantation of the implanted mechanical/hydraulic
urinary continence device. Improper device handling (including cutting
or nicking of the device) can lead to device malfunctions. Inadequate
pressure within the system (due to selection of incorrect cuff or
reservoir size) results in either incontinence (due to inadequate
urethral closing pressure) or outflow obstruction (due to excessive
urethral closing pressure), both of which lead to the need for
reoperation (Refs. 7, 12, 30, and 34). This may be due to a lack of
guidance for determining the appropriate device size for an individual
patient (Refs. 2, 9, 25, 31, and 48). Erosion secondary to infection,
can be caused by intraoperative field contamination or urethral or
vaginal injury (Refs. 26 and 42). Finally, intraoperative and
postoperative kinks in the tubing can occur due to incorrect tubing
length (Ref. 7) and result in a low urethral closure pressure (Refs. 9,
34, and 48).
5. Hydronephrosis
Hydronephrosis refers to the dilation of the upper urinary tract as
a result of chronic obstruction to urine outflow, which can lead to
kidney damage. Some authors have reported an elevated incidence of
hydronephrosis following implantation of the implanted mechanical/
hydraulic urinary continence device (Refs. 49 through 52). This
complication has mostly occurred when the device is implanted in
patients with myelopathy. It has been theorized that the development of
hydronephrosis is due to a combination of slight detrusor hyperreflexia
and low bladder capacity (Ref. 49). Other researchers have noted the
development of detrusor hypertonicity after implantation, leading to
hydronephrosis (Ref. 52). The pathogenesis and incidence of this risk
is unknown and requires further study.
6. Human Carcinogenicity
Carcinogenesis has been widely discussed as a reputed risk
secondary to implantation of any material. Evidence from the literature
indicates that in animal studies, different forms of silicone have been
associated with various types of cancer (Refs. 53 through 57). Cases of
several types of cancer in humans have been reported in association
with various forms of implanted silicone (Refs. 58 through 61).
7. Human Reproductive and Teratogenic Effects
The effect of certain silicone compounds on the reproductive
potential of the male is largely unknown. Le Vier and Jankowiak report
that at least one form of organosiloxane, which is known to be present
in some silicone gels, mimics estrogens in the male rat, leading to
rapid testicular atrophy (Ref. 62).
Teratogenesis includes the origin or mode of production of a
malformed fetus and the disturbed growth processes involved in the
production of a malformed fetus. Studies using silicone fluid in
animals have been minimal, and yield contradictory and inconclusive
results (Refs. 63 through 65). Prolonged contact with either silicone
elastomer, or silicone gel-filled membrane in devices containing
silicone gel, presents a potential risk of teratogenicity in humans.
Further study of these risks is necessary.
8. Immune Related Connective Tissue Disorders--Immunological
Sensitization
Immunological sensitization may be a serious risk associated with
an implanted mechanical/hydraulic urinary continence device. Recent
clinical data have shown that silicone elastomers are capable of
producing immune responses (Ref. 66). Immune related connective tissue
disorders have also been reported in women who have silicone gel-filled
devices or who have had silicone injections in augmentation
mammoplasty. There are clinical reports of several patients who have
undergone augmentation mammoplasty with silicone gel-filled breast
prostheses and later presented with connective tissue disease-like
syndromes (Ref. 67). Recently, Naim et. al. conducted studies in rats
which demonstrated that silicone gel is a potent immunological adjuvant
(Ref. 68). Because implanted mechanical/hydraulic urinary continence
devices may consist of similar silicone elastomers and gels,
[[Page 8599]] further study of the potential risk of immune related
connective tissue disorders in humans with these implants is warranted.
9. Biological Effects of Silica
Amorphous (fumed) silica is bound to the silicone in the elastomer
of the implanted mechanical/hydraulic urinary continence device, and
may be fibrogenic and immunogenic. Fumed silica and the silicone
elastomer each elicit cellular responses in rats (Ref. 69). Researchers
have reported that there is an association between industrial exposure
to silica and development of systemic lupus erythematosus (Ref. 41).
The biological effects of silica, particularly the immunologic
component of these reactions, present a potential risk for device
recipients and need to be examined.
10. Silicone Particle Shedding, Silicone Gel Leakage, and Associated
Migration
Silicone particle shedding and subsequent migration have been
reported with genitourinary prosthetic devices, including implanted
mechanical/hydraulic urinary continence devices (Refs. 70 and 71).
Silicone gel leakage and migration from the silicone elastomer
envelope, either from rupture of the envelope or by leaking of the gel
through the envelope (gel ``bleed''), are also potential significant
risks of implanted mechanical/hydraulic urinary continence devices
containing silicone gel. Rupture of the envelope with gel leakage and
subsequent migration may be secondary to surgical technique, or may
result from mechanical stresses such as device usage, trauma, and wear
on the envelope, and necessitates removal of the implant. In addition,
silicone gel-filled breast implants are reported to ``bleed'' micro
amounts of silicone through the intact silicone elastomer shell into
the surrounding tissues (Refs. 72 through 81). Furthermore,
fluorosilicone gels have been used to lubricate the inner surfaces of
cuff shells (Ref. 36) and, therefore, are an additional source for gel
bleed. Although diffusion of silicone gel through the elastomer
envelope and silicone particle shedding have not specifically been
measured (e.g., quantified) in the implanted mechanical/hydraulic
urinary continence device, they have been reported (Ref. 70) and,
therefore, particle shedding and gel bleed continue to be potential
risks with this device and need to be evaluated. Migration of the
particles and gel into the human body presents the potential for
development of adverse effects such as granulomas, lymphadenopathy, or
cellular immune response (Refs. 41, 58, 59, 70, and 71). The ultimate
fate of migrating silicone particles or silicone gel within the body is
currently not well understood. It should be noted that the use of
silicone gel in these devices may have been discontinued.
11. Degradation of Polyurethane Elastomer
Polyurethane elastomer materials, which may be present in some
implanted mechanical/hydraulic urinary continence devices, may degrade
over time and release degradation products such as methylene diamine or
toluene diamine, which are potential carcinogens in animals (Refs. 82
and 83). FDA is not aware of any mechanical/hydraulic urinary
incontinence devices which currently use this material. This potential
risk is associated only with those implanted mechanical/hydraulic
urinary continence devices that contain polyurethane elastomers.
12. Degradation of Polyurethane Foam
This potential risk is associated only with those implanted
mechanical/hydraulic urinary continence devices that are covered with
polyurethane foam. The polyurethane foam material that has been used to
cover some devices is known to degrade over time with a potential
breakdown product of 2,4 diaminotoluene (TDA), a known carcinogen in
animals (Refs. 84 through 89). The fate of the degraded product in vivo
is unknown to date, and the use of this material in implanted
mechanical/hydraulic urinary continence devices may have been
discontinued. Case reports of polyurethane foam covered silicone gel-
filled breast implants indicate that there is greater difficulty with
the removal of this type of prosthesis due to fragmented polyurethane
shell and/or capsular tissue ingrowth (Refs. 90 through 96). Also,
foreign body response has been reported concurrent with the use of the
polyurethane foam covered testicular prosthesis in humans (Ref. 97).
13. Other Reported Complications
The following are among the additional risks which have also been
reported with the implanted mechanical/hydraulic urinary continence
device: perineal discomfort/pain (Refs. 10, 17, and 27); development of
bladder hyperreflexia (Refs. 98 through 100); worsening/persistence of
incontinence (Refs. 51, 99, and 100); urinary retention (Refs. 51 and
101); hematoma (Ref. 28); seroma (Ref. 44); inguinal hernia formation
(Ref. 102); fibrous capsule formation, failure of cuff to deflate,
broken tubing (Ref. 51); fistula formation from urethral erosion (Ref.
8); urethral scarring (Ref. 99); bleeding (Ref. 103); urethral
stricture requiring urethrotomy (Ref. 101); wound dehiscence, pelvic
abscess (Ref. 104); and fistula to the skin (Ref. 10).
F. Benefits of the Device
The implanted mechanical/hydraulic urinary continence device is
intended to provide intermittent or continuous pressure to occlude the
urethra, thereby restoring urinary continence. The device is indicated
in males or females whose urinary sphincter is dysfunctional.
Implants have been used to treat incontinence resulting from
prostatectomy, myelopathy (e.g., spina bifida, myelomeningocele),
spinal column injury, sacral agenesis/ dysgenesis, exstrophy/epispadias
syndrome, pelvic trauma, and other conditions.
Although there are adverse physiologic effects associated with
urinary incontinence (e.g., infection and skin irritation due to
exposure to urine) (Ref. 105), the incontinent patient's mental health
and quality of life can also suffer significantly. Incontinence can be
socially, psychologically, and physically debilitating (Refs. 43 and
106). A reduction of social activities and interactions can be
associated with the loss of urinary continence (Ref. 105). The loss of
self-esteem (Ref. 107) and emotional problems (Ref. 25) have also been
associated with this condition. Finally, some research has shown a
relationship between depression indices and incontinence (Ref. 105).
An implanted mechanical/hydraulic urinary continence device can
restore continence and may improve quality of life. Published studies
indicate a moderately high success rate for either restoring or
improving continence. Some of these studies have also noted that the
restoration of continence can improve quality of life (Refs. 20 and 38)
and self-esteem (Ref. 26).
G. Need for Information for Risk/Benefits Assessment of the Device
As the above sections indicate, there is reasonable identification
of the risks and benefits associated with the implanted mechanical/
hydraulic urinary continence device. There is, however, insufficient
valid scientific evidence to permit FDA to perform a risk/benefit
analysis. Therefore, FDA is now seeking further information on the
following safety and effectiveness issues associated with the implanted
mechanical/hydraulic urinary continence device: [[Page 8600]]
(1) Long-term safety and effectiveness data for the device are
needed. The incidence of implant failure and attendant causes, as well
as the incidence of reoperations required, have not been clearly
determined. Such device failures include, but are not limited to:
Tissue erosion, infection, pain/discomfort, injury to the upper urinary
tract due to either urinary retention or hydronephrosis, continued or
worsened incontinence secondary to implantation of the implanted
mechanical/hydraulic continence device, leakage, wear, tubing kinking/
breaking or disconnection, pump failure, and cuff or pad failure. Also,
the incidence rates of hematoma, seroma, inguinal hernia formation,
fibrous capsule formation, fistula formation from urethral erosion,
urethral scarring, bleeding, urethral stricture, development of bladder
hyperreflexia, wound dehiscence, pelvic abscess, and fistula to the
skin are poorly understood and need to be studied. Particularly, it is
not well known whether the increased urethral resistance afforded by
implanted mechanical/hydraulic urinary continence devices eventually
leads to chronic upper urinary tract damage (e.g., hydronephrosis and/
or worsening of renal function). This risk is especially a concern for
young patients, who are most likely to have the device in place for
many years.
(2) It is unknown for which subgroups of the population with
urinary incontinence the benefits of the implanted mechanical/hydraulic
continence device outweigh the attendant risks, especially since other
voiding abnormalities, such as bladder dysfunction (detrusor
instability and poor compliance) and reflux often coexist with
sphincteric insufficiency. Factors which may increase the rate of
complications include the etiology and duration of incontinence, age,
gender, concomitant medical conditions, various anatomical
abnormalities, patient motivation and manual dexterity, and prior
treatments for the disorder, including prior surgery. An appropriate
risk/benefit analysis is needed for each subgroup for whom the device
will be indicated.
(3) The required presurgical workup of patients prior to device
implantation, including the diagnostic tests to demonstrate significant
sphincteric insufficiency which could be treated with the prosthesis,
must be clarified. In particular, the proper patient selection and
screening processes need to be developed and studied. Since some
adverse events, such as persistent urinary incontinence, may be
associated with other coexisting urodynamic abnormalities (e.g.,
bladder dysfunction), these abnormalities must be effectively diagnosed
prior to device implantation (Refs. 7, 22, and 108). The increased risk
of hydronephrosis among device recipients whose bladders are unable to
store urine at low pressures underscores the importance of thorough
preoperative patient evaluation with special attention to bladder
function and urodynamics (Ref. 103). Additionally, because the adverse
events that may occur following implantation of the device may not be
reversible, investigation is needed to determine which prior
conservative therapies a patient should have failed before being
considered an appropriate candidate for an implanted mechanical/
hydraulic continence device.
(4) The long-term effects of devices implanted in pediatric
patients need to be investigated. Currently, the relationship between
patient growth and the need for implanted mechanical/hydraulic
continence device revision or replacement is poorly understood and
warrants further study. While some researchers report no effects
related to the growth of the child, others report the potential for an
effect upon both the growth/morphology of the organs in the urinary
tract, as well as sexual development and function in children (Refs. 24
and 109).
(5) The effects of the implanted mechanical/hydraulic continence
device upon male sexual function are poorly understood. In particular,
the effect of the device upon erectile function needs to be examined.
(6) Since women of childbearing age are among the recipients of
implanted mechanical/hydraulic continence devices, the effects of the
device upon sexual function, pregnancy, and delivery must be analyzed.
(7) The effect of device implantation upon future medical diagnoses
and treatments needs to be examined. Currently, it is not well
understood whether the device's presence interferes with the ability to
diagnose and treat disorders affecting the organs or structures in
proximity to the implant components.
(8) The potential risks associated with silicone particle shedding
and silicone gel leakage, and the subsequent migration of the particles
and gel, need further clarification. This would include consideration
of gel cohesiveness, envelope thickness/strength, gel bleed, and the
role that the physical, mechanical, and chemical characteristics of
silicone elastomers and gels play in the immediate or long-term wear of
implanted mechanical/hydraulic urinary continence devices. (The
agency's concerns regarding silicone gel relate specifically to devices
with gel-filled components, such as certain models of the implanted
static pressure pad.)
(9) The potential long-term adverse effects of implanted
mechanical/hydraulic urinary continence devices, such as cancer, immune
related connective tissue disorders, and reproductive and teratogenic
effects, are unknown. Likewise, in polyurethane elastomer and/or
polyurethane foam covered implanted mechanical/hydraulic urinary
continence devices (known to be applicable to certain models of the
implanted static pressure pad), the long-term effects of the
polyurethane material (such as mechanical integrity and
carcinogenicity) are not understood. The agency notes that neither the
silicone particles, which may shed from the device (Refs. 70, 110, and
111), nor the chemical forms of silicone monomers and oligomers, or
additives (including catalysts, antioxidants, fillers, reinforcers, and
other processing agents), which may leach from the device, have been
characterized, and their metabolic fates are not known (Ref. 64).
Furthermore, no satisfactory independent study has thoroughly evaluated
the chronic long-term toxicity of silicone elastomers and their
derivatives. Because children are among the potential recipients of
these implants, information regarding the chronic toxic effects,
including possible reproductive and teratogenic effects, of silicone
could be of substantial importance in determining the risk to these
patients and their offspring.
(10) The malfunction rate and longevity reported for implanted
mechanical/hydraulic urinary continence devices have generally not
reflected the predictions of preclinical testing. Further investigation
is warranted to determine how the laboratory and animal studies can be
designed to more accurately predict device reliability under actual
conditions of use.
FDA believes, therefore, that the implanted mechanical/hydraulic
urinary continence device should undergo premarket approval to obtain
valid scientific evidence in order for FDA to determine whether the
risks of using the device are adequately balanced by its benefits.
II. PMA Requirements
Any PMA for the device must include the information required by
section 515(c)(1) of the act and the implementing provisions under 21
CFR 814.20. Such a PMA shall include a [[Page 8601]] detailed
discussion, accompanied by the results of applicable preclinical and
clinical studies, of the above identified risks and the effectiveness
of the device. In particular, the PMA shall include all known or
otherwise available data and other information regarding: (1) Any risks
known or should be reasonably known to the applicant that have not been
identified in this document; and (2) the effectiveness of the specific
implanted mechanical/hydraulic urinary continence device that is the
subject of the application.
Valid scientific evidence, as defined in Sec. 860.7 (21 CFR 860.7),
addressing the safety and effectiveness of the device should be
presented, evaluated and summarized in a section or sections of the PMA
separate from known or otherwise available safety and effectiveness
information that does not constitute valid scientific evidence (e.g.,
isolated case reports, random experiences, etc.).
A. Manufacturing Information
All manufacturing information for the device should be completely
described. The information should include but, is not necessarily
limited to, the chemical formulation and manufacturing procedures and
processes, presented in a step-by-step manner from the starting
materials to the finished product, including, but not limited to, all
nonreactants (such as antioxidants, light stabilizers, plasticizers,
i.e., anything added to polymer resins that is necessary for processing
of the finished product) and reactants (including catalysts, curing
agents, and intermediate precursors) for the pad (including
polyurethane foam covering, if applicable), cuff, pump, reservoir,
tubing, and all internal components, adhesives, colorants, lubricants,
and filling agents (e.g., gel, saline, contrast medium, etc.). A
complete master list of the common chemical names and alternate names
(manufacturer's trade name or code) for all nonreactants, reactants
(including intermediate precursors), additives, catalysts, adjuvants,
and products should be provided.
Chemical characterization of the elastomer intermediates (i.e.,
network precursors) of the pad (including polyurethane foam covering,
if applicable), cuff, pump, reservoir, tubing, and internal gel (if
applicable) sufficient to demonstrate control of the chemical
processing of the device materials should be provided. This should be
based on lot-to-lot comparisons (10 consecutive lot minimum) of the
following information: (1) The molecular weight distribution, expressed
as weight average molecular weight, number average molecular weight,
peak molecular weight, polydispersity, and viscosity average molecular
weight of these precursors; (2) analyses for volatile and nonvolatile
(if applicable) compounds, such as cyclic oligomers; (3) when viscosity
is used as the variable that is measured for production control, a
comparison of viscosity, number average molecular weight, and volatile
content; and (4) isocyanate content, acidity, isomer ratios, hydroxyl
number, water content, acid number, and peroxide content (where
applicable). Documentation establishing the extent of cross-linking
(where applicable) in the materials of the pad, cuff, pump, reservoir,
tubing, and all internal components and filling agents, or the
silicone-hydride and vinyl content of cross-linked materials of the
pad, cuff, pump, reservoir, tubing, and all internal components and
filling agents, as well as the particle size and surface area of the
silica if present in the pad, cuff, pump, reservoir, tubing, and the
composition of all internal components, filling agents, or gel should
be provided. A complete description of the medium used to inflate the
device (saline, contrast medium, etc.) and whether and how the implant
will be prefilled must also be provided.
The standard operating procedures for sterility and materials
qualifications must be provided. Sterilization information should
include the method of sterilization; the detailed sterilization
validation protocol and results; the sterility assurance level; the
type of packaging; the packaging validation protocol and results;
residual levels of ethylene oxide, ethylene glycol, and ethylene
chlorohydrin remaining on the device after the sterilization quarantine
period, if applicable; and the radiation dose, if applicable.
A complete description of the functional testing of subassemblies
and finished products performed during the manufacturing process and
during quality assurance/quality control (QA/QC) testing must be
provided. Functional testing performed during manufacturing and QA/QC
procedures should detect any device flaws that could lead to short-term
failure and should demonstrate functional integrity of the device. A
QA/QC plan that demonstrates how raw materials, components,
subassemblies, and any filling agents will be received, stored, and
handled in a manner designed to prevent damage, mixup, contamination,
and other adverse effects must be provided. This plan shall
specifically include, but not necessarily be limited to, a record of
raw material, component, subassembly, and filling agent acceptance and
rejection, visual examination for damage, and inspection, sampling and
testing for conformance to specifications.
Written procedures for finished device inspection to assure that
device specifications are met must be provided. These procedures shall
include, but are not limited to, the requirement that each production
run, lot or batch be evaluated and, where necessary, tested for
conformance with device specifications prior to release for
distribution. A representative number of samples shall be selected from
a production run, lot or batch and tested under simulated use
conditions and to any extremes to which the device may be exposed.
Furthermore, the QA/QC procedures must include appropriate visual
testing of the packaging, packaging seal, and product. Sampling plans
for checking, testing, and release of the device shall be based on an
acceptable statistical rationale (21 CFR 820.80 and 820.160).
B. Preclinical Data
Complete identification and quantification of all chemicals,
including residual amine containing components, volatile and
nonvolatile silicone cyclics and oligomers below a molecular weight of
1,500 exhaustively extracted from each of the individual structural
components (pad, cuff, pump, reservoir, tubing, and any other
materials, lubricants, or filling agents) as they are found in the
final sterilized device should be reported. The solvents used for
extraction should have varying polarities and should include, but not
be limited to, ethanol/saline (1:9) and dichloromethane. Other, more
contemporary extraction techniques, such as supercritical fluid
extraction, may also be useful, at least for exhaustive extraction of
the silicone materials. Experimental evidence must be provided
establishing that exhaustive extraction is achieved with one of the
selected solvents, and the percent recovery, especially for the more
volatile components, must be reported. Extracts that may contain
oligomeric or polymeric species must have the molecular weight
distribution provided along with the number and weight average
molecular weight, and polydispersity. All experimental methodologies
must be described, and raw data (including instrument reports) must be
provided along with all chromatographs, spectrograms, etc. The limit of
detection (two times noise level) must be provided when the analyte of
interest is not detected. Laboratory test methods and animal
experiments used [[Page 8602]] in the characterization of the physical,
chemical (other than exhaustive extraction) and mechanical properties
of the device should be applicable to the intended use of the device in
humans. Infrared measurements of the surface of device components as
they occur in the final, sterilized product should be provided.
Biocompatibility testing data must be provided for all materials
(pad, cuff, pump, reservoir, tubing, filling agents, gels, lubricants,
and any other materials) in the implanted mechanical/hydraulic urinary
continence device, including all color additives (ink, dyes, markings,
etc.) used to fabricate the implanted mechanical/hydraulic urinary
continence device. FDA guidance on biocompatibility testing is
available in the document titled ``Tripartite Biocompatibility Guidance
for Medical Devices.'' A copy may be obtained upon request from the
Division of Small Manufacturers Assistance (HFZ-220), Center for
Devices and Radiological Health, Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857. Biocompatibility evaluation should
follow the methodology of tests for tissue contacting, long-term
internal devices.
Toxicological effects (e.g., cytotoxicity, mutagenicity, affects on
the immune system, and reproductive and developmental toxicity) should
be identified. Complete mutagenicity testing of extracts from the
finished, sterilized components of the device should be provided. These
tests should include the following: Bacterial mutagenicity, mammalian
mutagenicity, deoxyribonucleic acid (DNA) damage, and cell
transformation assay.
Acute, subchronic, and chronic toxicity studies using the chemicals
recovered by the above exhaustive extraction processes should be
provided in the evaluation of the long-term biocompatibility of the
device, including dose response and time to response as well as gross
and histopathological findings in tissues both surrounding implants and
distal to implant sites (lymph nodes, prostate, urethra, bladder,
ovaries/testes, liver, kidneys, lungs, uterus, etc.). Animal studies of
carcinogenicity, reproductive toxicity, teratogenicity, and later
effects on offspring must be performed using scientifically justified
test methods. These studies must include animal testing of the extracts
from the final sterilized device. Teratology/ reproductive testing of
the final sterilized device and extractables should be performed in an
appropriate species using validated methods. Furthermore, for those
devices that contain silicone gel, a subset of these studies must test
the compounds extracted from the materials of the sterilized device for
estrogen-like antigonadotropic activity in an appropriate animal model
using scientifically valid methods.
Pharmacokinetic/biodegradation studies of all materials contained
in the finished device should state all materials of toxicological
concern, such as amine, silicone, and fluorosilicone compounds. Of
special concern are questions regarding the ultimate fate, quantities,
sites/organs of deposition, routes of excretion, and potential clinical
significance of silicone shedding, retention, and migration. Data on
the distribution and metabolic fate of amine containing components,
silicone, and any other materials used in the manufacturing of the
device should be supplied.
Animal testing should also be conducted to study the effect of
implantation upon device function and material integrity. Complete
device chemical characterization and mechanical testing should be
performed after devices have been implanted in an appropriate animal
model for an appropriate length of time. Of special concern is the
material integrity of the pad, cuff, reservoir, pump, tubing, joints,
etc., which should be functionally tested and investigated using
electron microscopy. The results of this testing should be compared to
the failure rates noted during in vitro testing and clinical studies in
order to demonstrate that the animal model and study duration chosen
are appropriate.
For the implanted mechanical/hydraulic urinary continence device
designs that contain silicone gel, or employ a silicone gel as a
lubricant, the gel bleed performance of the device, as determined from
the results of measurements using a standard diffusion cell maintained
at a temperature simulating physiologic conditions using stirred,
physiologic saline as a receptacle medium for the bleed, must be
reported. Each variation in thickness or device design must be measured
to accurately determine diffusion coefficients (with appropriate time
dependencies). The chemical identification of the bleed product,
including, but not limited to, amine containing components, volatile
and nonvolatile silicone cyclics and oligomers below a molecular weight
of 1,500 and molecular weight distribution, must be reported.
For the polyurethane covered designs (foam or elastomer), FDA
believes that in vivo implant studies must be performed to identify and
determine the bioabsorption, distribution, and elimination of the
polyurethane covering (as well as their degradation products) in
experimental animals. It is also important to identify and determine
the mechanism and rate of degradation, as well as the quantity of TDA
or other products generated by the breakdown of polyurethane covered
implanted mechanical/hydraulic urinary continence devices after
prolonged exposure under physical conditions in animals. Additionally,
the agency recommends that retrospective epidemiological and
prospective clinical studies be designed to assess the potential of
cancer and other long-term complications related to implanted
mechanical/hydraulic urinary continence devices containing
polyurethane. The agency suggests that these preclinical and
epidemiological studies be conducted as a separate subset of implanted
mechanical/hydraulic urinary continence device safety studies.
In vitro testing should be conducted at the component, subassembly,
and final device levels and must examine all aspects of device design,
construction, and operation. This testing should also demonstrate how
the device design and manufacturing processes address the failure mode
and effects analysis. The failure mode effects analysis should be
provided. Copies of the original data sheets from all tests must be
included in the PMA. All device failures must be completely described,
and the corrective actions taken to eliminate or minimize further
recurrence should also be identified.
An adequate number of samples of each model, based on relevant
power calculations, will be required. If marketing approval is sought
for multiple device versions, each version requires its own set of
preclinical tests and results. If sample devices of each available size
are not tested, it must be clearly indicated which device sizes were
used for each test. The absence of testing on each size must be
justified by analysis demonstrating that the results from the tested
devices will accurately predict results for the untested device sizes.
The test conditions and acceptance criteria for all tests should be
completely explained and justified. All tests should be performed on
final, sterilized devices in an environment simulating the possible
range of anticipated in vivo conditions (temperatures, pressures,
forces, stresses, etc.), where possible. All methods used to determine
the condition of the device after testing, e.g., visual examination,
electrical [[Page 8603]] continuity, electron microscope examination,
functional testing, etc., must be discussed and justified.
All data collected from in vitro and animal testing, regarding the
useful lifetime or long-term reliability of the device, must be
compared to data from clinical studies (prospective and/or
retrospective) where the useful lifetime of the device has been
determined. This comparison must validate the ability of the in vitro
and animal tests to accurately predict the useful lifetime of the
implanted device.
If accelerated aging is used to demonstrate device durability and
reliability, all processes used should be completely described, and the
calculations validating the expected aging should be provided.
All physical, chemical, and functional properties of the device
should be completely characterized, and the design specifications must
be adequately justified. Chemical characterization should include,
where applicable, molecular weight and molecular weight distribution,
cross-link density, infrared analysis (free isocyanate content, side
reaction products), and differential scanning calorimetry. The physical
tests should include, but are not necessarily limited to the tests
discussed below.
Testing should include the following specific methods or their
equivalents: (1) American Society for Testing Materials (ASTM) Test
Method D412 to measure tensile strength, force to breakage, ultimate
elongation, and total energy to rupture of the pad, cuff, pump,
reservoir, tubing, and bulk of all elastomeric components (with and
without incorporated fold flaws) of the finished, sterilized device;
dynamic mechanical analysis and fatigue characterization of all
elastomeric components particularly those comprising the cuff of the
finished, sterilized device; (2) ASTM Test Method D624 to determine
tear and abrasion resistance of all components; an applied force at the
rate of 1 Hertz versus number of cycles to failure (AF/N) curve
(including the minimum force required to rupture the component under a
single stroke of applied load), constructed on the basis of cyclical
compression testing of intact sterilized devices; and (3) ASTM Test
Method F703 (section 7.2) to determine the force to break of adhered or
fused joints. A complete report of the cohesivity and penetration
testing of the gel must also be reported for the devices containing
silicone gel. The results of each of these tests must be compared to
the energy, forces, etc., that the device will encounter in vivo.
Life testing should demonstrate the device is sufficiently durable
to withstand the demands of use while maintaining operational
characteristics sufficient for urethral compression throughout the
expected operational lifetime of the implanted mechanical/hydraulic
urinary continence device, as stated in the physician and patient
labeling. Life testing should include measurements of all component and
material wear and bond strengths after the device is cycled between
inflated and deflated conditions. A discussion comparing the rate of
cycling performed in each test to the approximate maximum rate of
cycling of the device in vivo and to the expected longevity of the
implant should be included.
Appropriate ``downtimes'' at predetermined cyclical intervals
should be included in the life tests to evaluate relevant performance
characteristics and conformance to design specifications. Material
characteristics indicative of material degradation that could induce
device malfunction should be completely evaluated. Cyclical testing
beyond the expected longevity of the implant and recording of failure
mode must also be included as part of the life tests.
Filling agent permeability from the reservoir and body of the
device must be evaluated to demonstrate that fluid loss due to osmosis
will be acceptable over the expected life of the implanted mechanical/
hydraulic urinary continence device.
Component-specific tests are also necessary. Reliability over the
expected life of the device, proper operation, and conformance to
predetermined operational specifications must be demonstrated for each
component. Resistance of each component to abrasion, tear, crazing,
fracture, material fatigue (including wear between each component),
change of position (e.g., valve seats), and permanent deformation also
must be demonstrated.
Pad characterization and testing should include, but not be limited
to: Measurement of stiffness and rigidity, including resistance to
buckling; uniformity of dimensions (if the device is inflated); and
wear characteristics.
Cuff characterization and testing should include, but not be
limited to: Maximum pressure and expansion capability; measurement of
stiffness, including resistance to buckling; resistance to aneurysms;
ability of cuff closure to remain inflated under maximum loads expected
in vivo; uniformity of inflated dimensions; inflation and deflation
characteristics; and wear characteristics at folds in the cuff.
Pump characterization and testing should include, but not be
limited to: The range of volumes displaced per stroke; minimum force
required to affect fluid displacement; squeeze force versus fluid
displacement; inflation effort, defined as pump force times the number
of strokes required for full device activation; and ability of the
implanted mechanical/hydraulic urinary continence device to maintain
its set pressure after repeated punctures to its pressure adjustment
port with both new devices and devices evaluated in the reliability
tests.
Valve characterization and testing should include, but not be
limited to: Pump output pressure required to affect valve opening for
device activation; tactile pressure/force required to affect valve
opening, against fully inflated cuffs, for deflation; back pressure
required for valve failure; maximum pressure differential across closed
valve at full inflation and deflation, and the leakage rates at these
pressures; prevention of spontaneous deflation under movements and
loads simulating those expected to be sustained by the implanted device
in an inflated state; and potential for valve failure which could
result in an inability to inflate or deflate the cuff.
Reservoir characteristics should be evaluated and should include,
but not be limited to: Volume capacity; pressures generated over the
inflation/deflation cycle; rate of maximum fluid outflow and inflow;
wear characteristics if a fold in the reservoir envelope occurs; and
durability tests demonstrating adequate resistance to fatigue caused by
cyclic external compression applied radially to inflated reservoir.
Tubing testing should include, but not be limited to: Tensile
characteristics (with and without tubing connectors, if any); tear or
rupture resistance; kink resistance; wear characteristics if a fold in
the tubing develops; and ability of the tubing to remain intact under
loads simulating and exceeding those expected in vivo.
Testing to demonstrate the inflation/deflation characteristics of
the device should include, but not be limited to: Amount of pressure
generated during inflation of the cuff; amount of pressure drop
(deflation) and rise (inflation) per unit time; ability to maintain the
inflated cuff dimensions; and time to fully inflate and deflate the
cuff from specified starting pressures.
All bonds within the device and between components should undergo
appropriate testing including, but not be limited to measurement of
bond shear and tensile strength. Bond strength [[Page 8604]] should
exceed the loads expected during device handling and after
implantation.
Other components of the implanted mechanical/hydraulic urinary
continence device or accessories, such as tubing connectors, extension
adapters, and specialized tools used during the insertion procedure,
should be evaluated appropriately. Testing of these components or
accessories should reflect the anticipated conditions of use; for
example, tubing connectors should be demonstrated to be able to
maintain connection to the device for the expected life of the device.
C. Clinical Data
Valid scientific evidence, as defined in Sec. 860.7(c)(2), which
includes information from well-controlled investigations, partially
controlled studies, studies and objective trials without matched
controls, well-documented case histories conducted by qualified experts
and reports of significant human experience with a marketed device from
which it can fairly and responsibly be concluded by qualified experts
that there are reasonable assurances of the safety and effectiveness of
the implanted mechanical/hydraulic urinary continence device. Detailed
protocols for the clinical trials, with explicit patient inclusion/
exclusion criteria and well-defined followup schedules, should be
specified. FDA believes that 5-year followup data are necessary in
order to characterize the safety and effectiveness of the device over
its expected lifetime; however, appropriately justified alternate
followup schedules will be considered. Any deviations from the protocol
should be stated and justified. Time-course presentations of
restoration of continence (dryness) or significant improvement in
continence, as well as other information on the anatomical and
physiological effects of the implanted mechanical/hydraulic urinary
continence device (including all adverse events) should be provided.
Full patient accounting should be reported, including: (1) Theoretical
followup (the number of patients that would have been examined if all
patients were examined according to their followup schedules); (2)
patients lost to followup, excluding deaths, should include measures
taken to minimize such events (with all available information obtained
on patients lost to followup) and should not exceed 20 percent over the
course of the study; (3) time course of revisions, including all
explant and repair data; and (4) time-course of deaths (stating the
cause of death, including the reports from any postmortem
examinations). As part of this patient accounting, each clinical report
should clearly state the date that the data base was closed to the
addition of new information. Detailed patient demographic analyses and
characterizations should be presented to show that the patients
enrolled in the study are representative of the population for whom the
device is intended.
A statistical demonstration, based on the number of patients who
complete the required study period, should show that the sample size of
the clinical study is adequate to provide accurate measures of the
safety and effectiveness of this device. The statistical demonstration
should identify the effect criteria, clinically reasonable levels for
Type I (alpha) and Type II (beta) errors, and anticipated variances of
the response variables. The statistical demonstration should also
provide any assumptions made and all statistical formulas used (with
copies of any references). A complete description of all patient
randomization techniques used, and how these techniques were employed
to exclude potential sources of bias, should be provided. Statistical
justifications for pooling across several demographic or surgical
variables, such as the etiology and duration of incontinence, age,
gender, concomitant medical conditions, various anatomical
abnormalities, the type or model of the device implanted, the number
and type of treatments (if any) attempted to restore continence prior
to device implantation, device usage (initial implantation versus
revision), investigational site, degree of patient motivation and
manual dexterity, surgeon experience and technique, and pad or cuff
placement site, should be provided. The data collected and reported
should include all necessary variables in order to permit
stratification and analysis of the study data required to evaluate the
risk/benefit ratio for each clinically relevant subpopulation of
patients.
Appropriate concurrent control/comparison groups should be included
and justified and, if not, their absence must be justified. All
hypotheses to be tested must be clearly stated. Appropriate statistical
techniques must be employed to test these hypotheses as support for
claims of safety and effectiveness. For each relevant subgroup, a
sufficient number of patients need to be followed for a sufficient
length of time to support all claims (explicit and implied) in any PMA
submission.
To evaluate the risks to the patient from the implanted mechanical/
hydraulic urinary continence device, clinical studies should include
time-course presentations of clinical data demonstrating the presence
or absence of tissue erosion, infection, pain/discomfort, injury to the
upper urinary tract due to either urinary retention or hydronephrosis,
continued or worsened incontinence, leakage, wear, tubing kinking/
breaking or disconnection, pump failure, cuff or pad failure, hematoma,
seroma, inguinal hernia formation, fibrous capsule formation, fistula
formation from urethral erosion, urethral scarring, bleeding, urethral
stricture, development of bladder hyperreflexia, reoperation, wound
dehiscence, pelvic abscess, and fistula to the skin, including any
effects on the immune system (both local to the device and systemic)
and the reproductive system, without regard to the device relatedness
of the event. The diagnostic criteria for each type of immunological
and allergic phenomenon should be defined at the beginning of the
study, and all cases should be well-documented utilizing these
criteria. Patients must be regularly monitored for the occurrence of
such adverse events for a minimum of 5 years post-implantation, or
until physical maturity of the subject (whichever occurs later).
The effectiveness of the device may be assessed by an objective and
standardized recording/measurement of: (1) The ability of the device in
vivo to either restore or significantly improve urinary continence; and
(2) the enhancement of a patient's quality of life following
implantation of the device; both of which should be balanced against
any risk of illness or injury from use of the device. FDA understands
that evaluation of the degree of benefit involves, in part, an
assessment of patient quality of life, which relates to the
postoperative function of the device. Such evaluation includes
subjective factors and relates to patient expectations. Assessments of
the in vivo performance of the device's function, on the other hand,
should provide some objective measure of device effectiveness.
Documentation of the anatomical and physiologic outcomes of
implantation of an implanted mechanical/hydraulic urinary continence
device shall include:
(1) Regular postsurgical evaluations of the functional (i.e.,
inflation and deflation) characteristics of the device for at least 5
years postimplantation, or until physical maturity of the subject
(whichever occurs later);
(2) Periodic postsurgical urodynamic testing (such as measurements
of leak point pressure and the volume of urine leaked into a pad after
a standard set of [[Page 8605]] maneuvers) during this followup period,
with comparisons to baseline measurements;
(3) Regular postsurgical assessments of incontinence grade
(possibly obtained from patient voiding diaries or the number of pads
required per day to keep dry), as compared to baseline values; and
(4) Patient assessments of the mechanical function of the implant
(such as ease of activation) during this followup period (which may be
influenced by the manual dexterity or motivation of the patient).
Documentation of the effect of the device upon the patient's
quality of life shall include:
(1) Prospective research designs, including pre- and postsurgical
repeated measures for at least 5 years postimplantation, or until
physical maturity of the subject (whichever occurs later);
(2) Standardized test questions rather than informal, yet-validated
questionnaires; and
(3) Comparisons of the postsurgical scores to those measured prior
to device implantation.
Any PMA for the implanted mechanical/hydraulic urinary continence
device should separately analyze the degree of device safety and
effectiveness by the following variables: (1) Etiology; (2) duration
and degree of urinary incontinence; (3) the device type or model
implanted; (4) gender; and (5) age. Furthermore, for each explantation
procedure performed on the study subjects, the following information
must be provided: (1) The mode of failure of the removed device; (2)
whether or not the explanted device was replaced with a new device; and
(3) either the manufacturer, type and model of the new device implanted
(if another implanted mechanical/hydraulic urinary continence device
was implanted), or the type of treatment (if any) that the patient
received for his/her incontinence (if revision surgery was not
performed). Additionally, the effect of the presence of these implants
upon future medical diagnoses/treatments involving the lower pelvic
region in recipients of implanted mechanical/hydraulic urinary
continence devices must be analyzed. Furthermore, any accessories sold
with the implanted mechanical/hydraulic urinary continence device must
be shown to have been effectively used in implant procedures without
adverse effects. Finally, each clinical investigation should validate
the physician and patient instructions for use (labeling) that were
used, particularly the instructions regarding the selection of the
appropriate device size (if applicable).
For polyurethane foam covered implants, the following additional
information needs to be presented:
(1) The kinetics of end products generated from the degradation of
the polyurethane material (in vivo);
(2) The frequency and incidence of infection and complication of
retrieval of the implant by surgeons; and
(3) The neoplasticity of these materials and products, as well as
their general toxicity, including neurological, physiological,
biochemical, and hematological effects, as well as pathology following
prolonged and repeated exposure to polyurethane foam covered implanted
mechanical/hydraulic urinary continence devices.
Any epidemiological studies submitted should contain sufficient
subjects to permit detection of a small, but clinically significant,
increase in one or more connective tissue diseases (especially
scleroderma) that may be associated with the use of the device.
The agency believes that insufficient time has elapsed to permit a
direct evaluation of the risks of cancer and immune related connective
tissue disorders posed by the presence of silicone in the human body,
and that insufficient epidemiological and experimental animal data are
available to make a reasonable and fair judgment of these risks.
Furthermore, the potential long-term risk of hydronephrosis and/or
decreases in renal function in patients implanted with the implanted
mechanical/hydraulic urinary continence device, due to the chronic
elevation of urethral resistance experienced postimplantation, has yet
to be quantified and is a concern of the agency. Therefore, the agency
will require long-term postapproval followup for any implanted
mechanical/hydraulic urinary continence device permitted in commercial
distribution. Well-designed clinical prospective studies with long-term
followup together with experimental animal studies will be considered
essential to the determination of the safety and effectiveness of the
device. Further, these clinical studies must collect long-term data on
the reproductive/teratogenic effects of the device as well as on the
later effects on the offspring.
The risk/benefit assessment (as with the entire PMA) must rely on
valid scientific evidence as defined in Sec. 860.7(c)(2) from well-
controlled studies as described in Sec. 860.7(f) in order to provide
reasonable assurance of the safety and effectiveness of the implanted
mechanical/hydraulic continence device in the treatment of urinary
incontinence.
D. Labeling
Copies of all proposed labeling for the device including any
information, literature, or advertising that constitutes labeling under
section 201(m) of the act (21 U.S.C. 321(m)), should be provided. The
general labeling requirements for medical devices are contained in 21
CFR part 801. These regulations specify the minimum requirements for
all devices. Additional guidance regarding device labeling can be
obtained from FDA's publication ``Labeling: Regulatory Requirements for
Medical Devices,'' and from the Office of Device Evaluation's ``Device
Labeling Guidance''; both documents are available upon request from the
Division of Small Manufacturers Assistance (address above). Highlighted
below is additional guidance for some of the specific labeling
requirements for implanted mechanical/hydraulic urinary continence
devices.
The intended use statement should include the specific indications
for use and identification of the target populations. Specific
indications and target populations must be completely supported by the
clinical data described above. For example, it may be necessary to
restrict the intended use to patients who have failed prior less
invasive therapies and/or to patients with specific etiologies of
incontinence in whom safety and effectiveness have been demonstrated.
The directions for use should contain comprehensive instructions
regarding the preoperative, perioperative, and postoperative procedures
to be followed. This information includes, but is not necessarily
limited to: (1) A description of any preimplant training necessary for
the surgical team; (2) a description of how to prepare the patient
(e.g., prophylactic antibiotics), operating room (e.g., what supplies
must be on hand), and implanted mechanical/hydraulic urinary continence
device (e.g., handling instructions, resterilization instructions) for
device implantation; (3) instructions for implantation, including
possible surgical approaches, sizing, fluid adjustment (including what
filling solutions may be used and how they must be prepared), device
handling, and intraoperative test procedures to ensure implant
functionality and proper placement; and (4) instructions for followup,
including whether antibiotic prophylaxis is recommended during the
postimplant period and/or during any subsequent dental or other
surgical procedures, how to determine when [[Page 8606]] patients are
ready to activate the device, and how to evaluate, and how often to
evaluate, proper functionality and placement. The directions should
instruct caregivers to specifically question patients prior to surgery
for any history of allergic reaction to any of the device materials or
filling agents. Troubleshooting procedures should be completely
described. The directions for use should incorporate the clinical
experience with the implant, and should be consistent with those
provided in other company-provided labeling.
The labeling should include both implant and explant forms to allow
the sponsor to adequately monitor device experience. The explant form
should allow collection of all relevant data, including the reason for
the explant, any complications experienced and their resolution, and
any action planned (e.g., replacement with another implant).
Patient labeling must be provided which includes the information
needed to give prospective patients realistic expectations of the
benefits and risks of device implantation. Such information should be
written and formatted so as to be easily read and understood by most
patients and should be provided to patients prior to scheduling
implantation, so that each patient has sufficient time to review the
information and discuss it with his or her physician(s). Technical
terms should be kept to a minimum and should be defined if they must be
used. Patient information labeling should not exceed the seventh grade
reading comprehension level.
The patient labeling should provide the patient with the following
information: (1) The indications for use and relevant
contraindications, warnings, precautions and adverse effects/
complications should be described using terminology well known and
understood by the average layman; (2) the anticipated benefits and
risks associated with the device must be provided to give patients
realistic expectations of device performance and potential
complications. The known, suspected and potential risks of device
implantation should be identified and the consequences, including
possible methods of resolution, should be described; (3) alternatives
available to the use of the device, including less invasive treatments,
should be identified, along with a description of the associated
benefits and risks of each. The patient should be advised to contact
his physician for more information on which of these alternatives might
be appropriate given his specific condition; (4) instructions for how
to use the device must be provided to the patient. This information
should include the expected length of recovery from surgery and when to
attempt activation following implantation, whether and how often the
device should be periodically cycled (if applicable), warnings against
certain actions that could damage the device, how to identify
conditions that require physician intervention, who to contact if
questions arise, and other relevant information; (5) the fact that the
implant should not be considered a ``lifetime'' implant must be
emphasized. Where possible, the patient labeling should provide
information on the approximate number of revisions necessary for the
average patient, and indicate the average longevity of each implant so
patients are fully aware that additional surgery for device
modification, replacement, or removal may be necessary. This
information must be supported by the clinical experience (i.e., not
merely bench studies) with the implant or by published reports of
experience with similar devices.
The physician's labeling should instruct the urologist or
implanting surgeon to provide the implant candidate with the patient
labeling prior to surgery to allow each patient sufficient time to
review and discuss this information with his physician(s).
The adequacy and appropriateness of the instructions for use
provided to physicians and patients should be verified as part of the
clinical investigations.
Applicants should submit any PMA in accordance with FDA's
``Premarket Approval (PMA) Manual.'' The manual is available upon
request from the Division of Small Manufacturers Assistance (address
above).
III. Comments
Interested persons may, on or before June 15, 1995, submit to the
Dockets Management Branch (HFA-305), Food and Drug Administration, rm.
1-23, 12420 Parklawn Dr., Rockville, MD 20857, written comments
regarding this proposal. Two copies of any comments are to be
submitted, except that individuals may submit one copy. Comments are to
be identified with the docket number found in brackets in the heading
of this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
Those wishing to make comments are encouraged to discuss all
aspects of the proposed findings regarding the following topics:
(1) Degree of risk, illness, or injury associated with the use of
the implanted mechanical/hydraulic urinary continence device;
(2) Laboratory, animal, and human studies required in a PMA for the
device in order to assess its safety and effectiveness;
(3) Feasibility of these studies within the time permitted by the
act, etc.; and
(4) Benefits to the public from the use of the device.
The comments must discuss in detail, for example, the reasons why
important new information on the safety and effectiveness of the device
could not feasibly be submitted within the time permitted, or why
animal studies may not be available to assess long-term effects such as
connective tissue disorders, or that carefully designed epidemiological
studies may not be available to evaluate the long-term silicone related
illnesses, etc.
The Center for Devices and Radiological Health staff are available
to provide guidance to manufacturers on any proposed laboratory,
animal, or epidemiological studies needed in a PMA.
IV. Opportunity to Request a Change in Classification
Before requiring the filing of a PMA or a notice of completion of a
PDP for a device, FDA is required by section 515(b)(2)(A)(i) through
(b)(2)(A)(iv) of the act and 21 CFR 860.132 to provide an opportunity
for interested persons to request a change in the classification of the
device based on new information relevant to its classification. Any
proceeding to reclassify the device will be under the authority of
section 513(e) of the act.
A request for a change in the classification of the implanted
mechanical/hydraulic urinary continence device is to be in the form of
a reclassification petition containing the information required by
Sec. 860.123 (21 CFR 860.123), including new information relevant to
the classification of the device, and shall, under section 515(b)(2)(B)
of the act, be submitted by March 2, 1995.
The agency advises that to assure timely filing of any such
petition, any request should be submitted to the Dockets Management
Branch (address above) and not to the address provided in
Sec. 860.123(b)(1). If a timely request for a change in the
classification of the implanted mechanical/hydraulic urinary continence
device is submitted, the agency will, by April 17, 1995, after
consultation with the appropriate FDA advisory committee and by an
order published in the Federal Register, either deny the request or
give notice of its intent to initiate a change in the
[[Page 8607]] classification of the device in accordance with section
513(e) of the act and 21 CFR 860.130.
V. References
The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
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4. Malloy, T. R., A. J. Wein, and V. L. Carpiniello, ``Surgical
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Sphincter,'' British Journal of Urology, 64(6):586-589, 1989.
31. Light, J. K., and F. B. Scott, ``Management of Urinary
Incontinence in Women With the Artificial Urinary Sphincter,'' The
Journal of Urology, 134(3):476-478, 1985.
32. Boyd, S. D., ``Role of Urethral Reconstruction and
Artificial Sphincter in Complicated Salvage Radical Prostatectomy,''
Urology, 32(4):304-308, 1988.
33. Marks, J. L., and J. K. Light, ``Male Urinary Incontinence.
What Do You Do?,'' Postgraduate Medicine, 83(7):121-127 and 130,
1988.
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Incontinence After Prostatectomy With the Artificial Urinary
Sphincter,'' The Journal of Urology, 142(2 pt 1):302-304, 1989.
35. Wang, Y., and H. R. Hadley, ``Experiences With the
Artificial Urinary Sphincter in the Irradiated Patient,'' The
Journal of Urology, 147(3):612-613, 1992.
36. Light, J. K., and J. C. Reynolds, ``Impact of the New Cuff
Design of Reliability of the AS800 Artificial Urinary Sphincter,''
The Journal of Urology, 147(3):609-611, 1992.
37. Rose, S. C., M. E. Hansen, G. D. Webster, C. Zakrzewski, R.
H. Cohan, and N. R. Dunnick, ``Artificial Urinary Sphincters: Plain
Radiography of Malfunction and Complications,'' Radiology,
168(2):403-408, 1988.
38. Scott, F. B., ``The Artificial Urinary Sphincter. Experience
in Adults,'' Urologic Clinics of North America, 16(1)105-117, 1989.
39. Varner, R. E., and J. M. Sparks, ``Surgery for Stress
Urinary Incontinence,'' The Surgical Clinics of North America,
71(5):1111-1134, 1991.
40. Carson, C. C., ``Infections in Genitourinary Prostheses,''
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43. Holt, S. A., and F. F. Bartone, ``Experience With the
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44. Kroovand, R. L., ``The Artificial Sphincter for Urinary
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45. Fishman, I. J., R. Shabsigh, and F. B. Scott, ``Experience
With the Artificial Urinary Sphincter Model AS800 in 148 Patients,''
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51. Medical Device Reporting (MDR) and Product Problem Reporting
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58. Benjamin, E., A. Ahmed, A. T. M. F. Rashid, and D. H.
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VI. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) 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.
VII. Analysis of Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).
Executive Order 12866 directs agencies to assess all costs and benefits
of available regulatory alternatives and, when regulation is necessary,
to select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the proposed
rule is not a significant regulatory action as defined by the Executive
Order and so is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because PMA's for this device could have been
required by FDA as early as June 30, 1986, and because firms that
distributed this device prior to May 28, 1976, or whose device has been
found by FDA to be substantially equivalent will be permitted to
continue marketing the implanted mechanical/hydraulic urinary
continence device during FDA's review of the PMA or notice of
completion of the PDP, the agency certifies that the proposed rule will
not have a significant economic impact on a substantial number of small
entities. Therefore, under the Regulatory Flexibility Act, no further
analysis is required.
List of Subjects in 21 CFR Part 876
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 876 be amended as follows:
PART 876--GASTROENTEROLOGY-UROLOGY DEVICES
1. The authority citation for 21 CFR part 876 continues to read as
follows:
Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j,
371).
2. Section 876.5280 is amended by revising paragraph (c) to read as
follows:
Sec. 876.5280 Implanted mechanical/hydraulic urinary continence
device.
* * * * *
(c) Date PMA or notice of completion of a PDP is required. A PMA or
notice of completion of a PDP is required to be filed with the FDA on
or before (insert date 90 days after the effective date of a final rule
based on this proposed rule), for any implanted mechanical/hydraulic
urinary continence device that was in commercial distribution before
May 28, 1976, or that has on or before (insert date 90 days after the
effective date of a final rule based on this proposed rule), been found
to be substantially equivalent to the implanted mechanical/hydraulic
urinary continence device that was in commercial distribution before
May 28, 1976. Any other implanted mechanical/hydraulic urinary
continence device shall have an approved PMA or declared completed PDP
in effect before being placed in commercial distribution.
Dated: January 10, 1995.
D.B. Burlington,
Director, Center for Devices and Radiological Health.
[FR Doc. 95-3805 Filed 2-14-95; 8:45 am]
BILLING CODE 4160-01-F