[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]



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

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.

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

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.
    1. Aliabadi, H., and R. Gonzalez, ``Success of the Artificial 
Urinary sphincter After Failed Surgery for Incontinence,'' The 
Journal of Urology, 143(5):987-990, 1990.
    2. Furlow, W. L., ``The Prosthetic Management of Urinary 
Incontinence,'' Seminars in Urology, 2(3):138-144, 1984.
    3. Herschorn, S., and S. B. Radomski, ``Fascial Slings and 
Bladder Neck Tapering in the Treatment of Male Neurogenic 
Incontinence,'' The Journal of Urology, 147(4):1073-1075, 1992.
    4. Malloy, T. R., A. J. Wein, and V. L. Carpiniello, ``Surgical 
Success With AMS M800 GU Sphincter for Male Incontinence,'' Urology, 
33(4)274-276, 1989.
    5. Riemenschneider, H. W., and S. G. Moon, ``Experience in 
Private Practice With the Implantable Artificial Urinary 
Sphincter,'' Ohio State Medical Journal, 79(8):630-633, 1983.
    6. Aaronson, I. A., ``The AS 800 Artificial Urinary Sphincter in 
Children With Myelodysplasia,'' South African Medical Journal, 
69(11):686-688, 1986.
    7. Barrett, D. M., and B. G. Parulkar, ``The Artificial 
Sphincter (AS-800). Experience With Children and Young Adults,'' 
Urologic Clinics of North America, 16(1)119-132, 1989.
    8. Hamilton, S., H. D. Flood, M. K. Shetty, and R. Grainger, 
``Radiology of the AS 800 Artificial Urinary Sphincter; Normal 
Appearances and Complications,'' European Journal of Radiology, 
13(2):122-125, 1991.
    9. Lowe, D. H., H. C. Scherz, and C. L. Parsons, ``Urethral 
Pressure Profilometry in Scott Artificial Urinary Sphincter,'' 
Urology, 31(1):82-85, 1988.
    10. Lukkarinen, O. A., M. J. Kontturi, T. L. Tammela, and P. A. 
Hellstrom, ``Treatment of Urinary Incontinence With an Implantable 
Prosthesis,'' Scandinavian Journal of Urology and Nephrology, 
23(2):85-88, 1989.
    11. Mundy, A. R., ``Artificial Sphincters,'' Review, British 
Journal of Urology, 67(3):225-229, 1991.
    12. Nurse, D. E., and A. R. Mundy, ``One Hundred Artificial 
Sphincters,'' British Journal of Urology, 61(4):318-325, 1988.
    13. Schreiter, F., ``Bulbar Artificial Sphincter,'' European 
Urology, 11(5):294-299, 1985.
    14. Scott, F. B., ``The Use of the Artificial Sphincter in the 
Treatment of Urinary Incontinence in the Female Patient,'' Urologic 
Clinics of North America, 12(2):305-315, 1985.
    15. West, J. R., ``The Artificial Urinary Sphincter. State-of-
the-Art Treatment for Urinary Incontinence,'' Arizona Medicine, 
41(4):244-247, 1984.
    16. Mundy, A. R., and T. P. Stephenson, ``Selection of Patients 
for Implantation of the Brantley Scott Artificial Urinary 
Sphincter,'' British Journal of Urology, 56(6):717-720, 1984.
    17. Perez, L. M., and G. D. Webster, ``Successful Outcome of 
Artificial Urinary Sphincters in Men With Post-Prostatectomy Urinary 
Incontinence Despite Adverse Implantation Features,'' The Journal of 
Urology, 148(2):1166-1170, 1992.
    18. Stone, A. R., and S. B. Radomski, ``Artificial Urinary 
Sphincter Reimplantation Following Cuff Erosion: Use of the Vaginal 
Approach,'' The Journal of Urology, 147(3):704-705, 1992.
    19. Aprikian, A., G. Berardinucci, J. Pike, and G. Kiruluta, 
``Experience With the AS-800 Artificial Urinary Sphincter in 
Myelodysplastic Children,'' Canadian Journal of Surgery, 35(4):396-
400, 1992.
    20. Sant Jeanne, P., ``Artificial Urinary Sphincter. Restoring 
Continence,'' AORN Journal, 43(4):866-875, 1986.
    21. Stephenson, T. P., A. R. Stone, J. Sheppard, and R. Y. 
Sabur, ``Preliminary Results of AS 791/792 Artificial Sphincter for 
Urinary Incontinence,'' British Journal of Urology, 55(6):684-686, 
1983.
    22. Foote, J., S. Yun, and G. E. Leach, ``Postprostatectomy 
Incontinence. Pathophysiology, Evaluation, and Management,'' 
Urologic Clinics of North America 18(2):229-241, 1991.
    23. Heathcote, P. S., N. T. Galloway, D. C. Lewis, and T. P. 
Stephenson, ``An Assessment of the Complications of the Brantley 
Scott Artificial Sphincter,'' British Journal of Urology, 60(2):119-
121, 1987.
    24. Khoury, A. E., and B. M. Churchill, ``The Artificial Urinary 
Sphincter,'' Pediatric Clinics of North America, 34(5):1175-1185, 
1987.
    25. Light, J. K., and F. B. Scott, ``The Artificial Urinary 
Sphincter in Children,'' British Journal of Urology, 56(1):54-57, 
1984.
    26. Mitchell, M. E., and R. C. Rink, ``Experience With the 
Artificial Urinary Sphincter in Children and Young Adults,'' Journal 
of Pediatric Surgery, 18(6):700-706, 1983.
    27. Motley, R. C., and D. M. Barrett, ''Artificial Urinary 
Sphincter Cuff Erosin. Experience With Reimplantation in 38 
Patients,'' Urology, 35(3):215-218, 1990.
    28. Swami, K. S., and P. Abrams, ``Artificial Urinary 
Sphincters,'' British Journal of Hospital Medicine, 47(8):591-596, 
1992.
    29. Goldwasser, B., W. L. Furlow, and D. M. Barrett, ``The Model 
AS 800 Artificial Urinary Sphincter: Mayo Clinic Experience,'' The 
Journal of Hospital Medicine, 137(4):668-671, 1987.
    30. Kil, P. J., J. D. De Vries, P. E. Van Kerrebroeck, W. 
Zwiers, and F. M. Debruyne, ``Factors Determining the Outcome 
Following Implantation of the AMS 800 Artificial Urinary 
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.
    34. Marks, J. L., and J. K. Light, ``Management of Urinary 
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,'' 
Urologic Clinics of North America, 16(1):139-147, 1989.
    41. Holmes, S. A., R. S. Kirby, and H. N. Whitfield, ``Urinary 
Tract Prostheses and Their Biocompatibility,'' The British Journal 
of Urology, 71(4):378-383, 1993.
    42. Webster, G. D., L. M. Perez, J. M. Khoury, and S. L. 
Timmons, ``Management of Type III Stress Urinary Incontinence Using 
Artificial Urinary Sphincter,'' Urology, 34(6):499-503, 1992.
    43. Holt, S. A., and F. F. Bartone, ``Experience With the 
Artificial Urinary Sphincter,'' The Nebraska Medical Journal, 
68(7):193-197, 1983.
    44. Kroovand, R. L., ``The Artificial Sphincter for Urinary 
Continence,'' Developmental Medicine and Child Neurology, 25(4):520-
523, 1983.
    45. Fishman, I. J., R. Shabsigh, and F. B. Scott, ``Experience 
With the Artificial Urinary Sphincter Model AS800 in 148 Patients,'' 
The Journal of Urology, 141(2)307-310, 1989.
    46. Scott, F. B., ``The Artificial Urinary Sphincter: Review and 
Progress,'' Medical Instrumentation, 22(4):174-181, 1988.
    47. Belloli, G., P. Campobasso, and A. Mercurella, ``Neuropathic 
Urinary Incontinence in Pediatric Patients: Management With 
Artificial Sphincter,'' Journal of Pediatric Surgery, 27(11):1461-
1464, 1992.
    48. Lorentzen, T., S. Dorph, and T. Hald, ``Artificial Urinary 
Sphincters. Radiographic Evaluation,'' ACTA Radiology, 28(1):63-66, 
1987.
    49. Bitsch, M., H. Nerstrom, J. Nordling, and T. Hald, ``Upper 
Urinary Tract Deterioration After Implantation of Artificial Urinary 
Sphincter,'' Scandinavian Journal of Urology and Nephrology, 
24(1):31-34, 1990.
    50. Light, J. K., and T. Pietro, ``Alteration in Detrusor 
Behavior and the Effect on Renal [[Page 8608]] Function Following 
Insertion of the Artificial Urinary Sphincter,'' The Journal of 
Urology, 136(3):632-635, 1986.
    51. Medical Device Reporting (MDR) and Product Problem Reporting 
(PPR), Device Experience Network (DEN), FDA.
    52. Roth, D. R., P. R. Vyas, R. L. Kroovand, and A. D. 
Perlmutter, ``Urinary Tract Deterioration Associated With the 
Artificial Urinary Sphincter,'' The Journal of Urology, 135(3):528-
530, 1986.
    53. Bischoff, F., and G. Bryson, ``Carcinogenesis Through Solid 
State Surfaces,'' Progress in Experimental Tumor Research, 5:85-133, 
1964.
    54. Hueper, W. C., ``Cancer Induction by Polyurethane and 
Polysilicone Plastics,'' Journal of the National Cancer Institute, 
33:1005-1027, 1964.
    55. Hueper, W. C., ``Carcinogenic Studies on Water-Soluble and 
Insoluble Macromolecules,'' Archives of Pathology and Laboratory 
Medicine, 67:589-617, 1959.
    56. Maekawa, A., T. Ogiu, H. Onodera, K. Furuta, C. Matsuoka, Y. 
Ohno, H. Tanigawa, G. S. Salmo, M. Matsuyama, and Y. Hayashi, 
``Malignant Fibrous Histiocytomas Induced in Rats by Polymers,'' 
Cancer Research and Clinical Oncology, 108:364-365, 1984.
    57. Pedley, R. B., G. Meachim, and D. F. Williams, ``Tumor 
Induction by Implant Materials,'' in Fundamental Aspects of 
Biocompatibility, vol. 2, edited by Williams, D. F., CRC Critical 
Reviews in Biocompatibility, CRC Press, Boca Raton, FL., pp. 176-
202, 1981.
    58. Benjamin, E., A. Ahmed, A. T. M. F. Rashid, and D. H. 
Wright, ``Silicone Lymphadenopathy: A Report of Two Cases, One With 
Concomitant Malignant Lymphoma,'' Diagnostic Histopathology, 5:133-
141, 1982.
    59. Digby, J. M., and A. L. Welles, ``Malignant Lymphoma With 
Intranodal Refractile Particles After Insertion of a Silicone 
Prostheses,'' Lancet, p.580, September 12, 1981.
    60. Morgenstern, L., S. H. Gleischman, S. L. Michel, J. E. 
Rosenberg, I. Knight, and D. Goodman, ``Relation of Free Silicone to 
Human Breast Carcinoma,'' Archives of Surgery, 120:573-577, 1985.
    61. Zafiracopoulos, P., and A. Rouskas, ``Breast Cancer at Site 
of Implantation of Pacemaker Generator,'' letter to the editor, 
Lancet, p. 1114, June 1, 1974.
    62. Le Vier, R. R., and M. E. Jankowiak, ``Effects of Oral 2,6-
cis-Diphenylhexamethylcyclotetrasiloxane on the Reproductive System 
of the Male Rat,'' Toxicology and Applied Pharmacology, 21:80-88, 
1972.
    63. Bates, H., R. Filler, and C. Kimmel, ``Developmental 
Toxicity Study of Polydimethylsiloxane Injection in the Rat,'' 
Teratology, 31:50A, 1985.
    64. Haley, T. J., ``Biocompatibility of Monomers,'' in Systemic 
Aspects of Biocompatibility, vol. 2, pp. 59-90, edited by Williams, 
D. F., CRC Series in Biocompatibility, Boca Raton, FL., 1981.
    65. Kennedy, G. L., M. L. Keplinger, and J. C. Calandra, 
``Reproductive, Teratologic, and Mutagenic Studies With Some 
Polydimethylsiloxanes,'' Journal of Toxicology and Environmental 
Health, 1:909-920, 1976.
    66. Goldblum, R. M., R. P. Pelley, A. A. O'Donell, D. Pyron, and 
J. P. Heggers, ``Antibodies to Silicone Elastomers and Reactants to 
Ventriculoperitoneal Shunts,'' Lancet, pp. 510-513, August 29, 1992.
    67. Varga, J., H. R. Schumacher, and S. A. Jimenez, ``Systemic 
Sclerosis After Augmentation Mammoplasty With Silicone Implants,'' 
Annals of Internal Medicine, 111:377-383, 1989.
    68. Naim, J. O., R. J. Lanzafame, and C. J. van Oss, ``The 
Adjuvant Effect of Silicone-Gel on Antibody Formation in Rats,'' 
Immunological Investigations, 22(2):151-161, 1993.
    69. Picha, G. J., and J. A. Goldstein, ``Analysis of the Soft-
Tissue Response to Components Used in the Manufacture of Breast 
Implants: Rat Animal Model,'' Plastic and Reconstructive Surgery, 
87:490-500, 1991.
    70. Barrett, D. M., D. C. O'Sullivan, A. A. Malizia, H. M. 
Reiman, and P. C. Abell-Aleff, ``Particle Shedding and Migration 
From Silicone Genitourinary Prosthetic Devices,'' The Journal of 
Urology, 146(2):319-322, 1991.
    71. Reinberg, Y., J. C. Manivel, and R. Gonzalez, ``Silicone 
Shedding From Artificial Urinary Sphincter in Children,'' The 
Journal of Urology, 150(2 pt 2):694-696, 1993.
    72. Baker, J. L., R. R. LeVier, and D. E. Spielvogel, ``Positive 
Identification of Silicone in Human Mammary Capsular Tissue,'' 
Plastic and Reconstructive Surgery, 69:56-60, 1982.
    73. Barker, D. E., M. I. Retsky, and S. Schultz, ``Bleeding of 
Silicone From Bag-gel Breast Implants, and Its Clinical Relation to 
Fibrous Capsule Reaction,'' Plastic and Reconstructive Surgery, 
61:836-841, 1978.
    74. Brody, G. S., ``Fact and Fiction About Breast Implant 
'Bleed','' Plastic and Reconstructive Surgery, 60:615-616, 1977.
    75. Gayou, R., and R. Rudolph, ``Capsular Contraction Around 
Silicone Mammary Prostheses,'' Annals of Plastic Surgery, 2(1):62-
71, 1979.
    76. Gibbons, D. F., J. M. Anderson, R. L. Martin, and T. Nelson, 
``Wear and Degradation of Retrieved Ultrahigh Molecular Weight 
Polyethylene and Other Polymeric Implants,'' in Corrosion and 
Degradation of Implant Materials edited by Syrett, B. C., and A. 
Acharya, American Society for Testing and Materials (ASTM), Kansas 
City, MO, Philadelphia ASTM, pp. 20-40, 1979.
    77. Hausner, R. J., F. J. Schoen, M. A. Mendez-Fernandez, W. S. 
Henly, and R. C. Geis, ``Migration of Silicone Gel to Auxiliary 
Lymph Nodes After Prosthetic Mammoplasty,'' Archives of Pathology 
Laboratory Medicine, 105:371-372, 1981.
    78. Jenny, H., and J. Smahel, ``Clinicopathologic Correlations 
in Pseudocapsule Formation After Breast Augmentation,'' Aesthetic 
Plastic Surgery, 5:63-68, 1981.
    79. Mandel, M. A., and D. F. Gibbons, ``The Presence of Silicone 
in Breast Capsules,'' Aesthetic Plastic Surgery, 3:219-225, 1979.
    80. Smahel, J., ``Foreign Material in the Capsules Around Breast 
Prostheses and the Cellular Reaction To It,'' British Journal of 
Plastic Surgery, 32:35-42, 1979.
    81. Wickham, M. G., R. Rudolph, and J. L. Abraham, ``Silicon 
Identification in Prosthesis-Associated Fibrous Capsules,'' Science, 
199:437-439, 1978.
    82. ``Bioassay of 2,4-Diaminotoluene for Possible 
Carcinogenicity,'' Bethesda, MD: National Institutes of Health, U.S. 
Department of Health, Education and Welfare, Publication 79-1718, 
1979.
    83. ``Carcinogenosis Studies of 4,4-Methylenedianiline 
Dihydrochloride (CAS No. 13552-44-8) in F344/N Rats and B6C3F1 Mice 
(Drinking Water Studies),'' National Toxicology Program, Technical 
Report Series No. 248, 1983.
    84. Foreign Compound Metabolism in Mammals, 5:212, 1979.
    85. Guthrie, J. L., and R. W. McKinney, ``Determination of 2,4 
and 2,6 Diaminotoluene in Flexible Urethane Foam,'' Analytical 
Chemistry, 49(12):1676-1680, 1977.
    86. International Agency for Research on Cancer, ``2,4- and 2,6-
Toluene, Diisocyanates,'' IARC Cancer Review, IARC Monographs on the 
Evaluation of the Carcinogenic Risk of Chemicals to Man 19:303, 
1979.
    87. International Agency for Research on Cancer, ``2,4-
Diaminotoluene,'' IARC Cancer Review, IARC Monographs on the 
Evaluation of the Carcinogenic Risk of Chemicals to Man, 16:83, 
1978.
    88. Lelah, M. D., and S. L. Cooper, Polyurethanes in Medicine, 
CRC Press, Inc., Boca Raton, FL, 1986.
    89. Lowe, A., ``The Chemistry of Isocyanates,'' Proceedings of 
the Royal Society of Medicine, 63:367-368, 1970.
    90. Cocke, W. M., H. K. Leathers, and J. B. Lynch, ``Foreign 
Body Reactions to Polyurethane Covers of Some Breast Prostheses,'' 
Plastic and Reconstructive Surgery, 58:527-530, 1975.
    91. Herman, S., ``Infection Surrounding Meme Implants,'' 
correspondence, Plastic and Reconstructive Surgery, 75:926, 1985.
    92. Jabaley, M. E., and S. K. Das, ``Late Breast Pain Following 
Reconstruction With Polyurethane-Covered Implants,'' Plastic and 
Reconstructive Surgery, 78:390-395, 1986.
    93. Slade, C. L., and H. D. Peterson, ``Disappearance of the 
Polyurethane Cover of the Ashley Natural Y Prostheses,'' Plastic and 
Reconstructive Surgery, 70:379-382, 1982.
    94. Smahel, J., ``Tissue Reactions to Breast Implants Coated 
With Polyurethane,'' Plastic and Reconstructive Surgery, 61:80-85, 
1982.
    95. Umansky, C., ``Infection With Polyurethane-coated 
Implants,'' correspondence, Plastic and Reconstructive Surgery, 
75:925, 1985.
    96. Wilkinson, T. S., ``Polyurethane-coated Implants,'' 
correspondence, Plastic and Reconstructive Surgery, 75:925-926, 
1985.
    97. Weissbach, L., ``Alloplastic Testicular Prostheses,'' in 
Genitourinary Reconstruction With Prostheses, edited by Wagenknecht, 
L. V., W. L. Furlow, and J. Auvert, Stuttgart, Georg Thieme, pp.173-
187, 1981.
    98. Bosco, P. J., S. B. Bauer, A. H. Colodny, J. Mandell, and A. 
B. Retik, ``The Long-Term Results of Artificial Sphincters in 
Children,'' The Journal of Urology, 146(2):396-399, 1991.
    99. Hald, T., ``The Artificial Sphincter in the Treatment of 
Congenital Incontinence,'' ACTA Urologica Belgica, 57(2):545-552, 
1989. [[Page 8609]] 
    100. Murray, K. H., D. E. Nurse, and A. R. Mundy, ``Detrusor 
Behaviour Following Implantation of the Brantley Scott Artificial 
Urinary Sphincter for Neuropathic Incontinence,'' British Journal of 
Urology, 61(2):122-128, 1988.
    101. Durrani, A. F., T. P. Rosenbaum, Shaw, P. J. R., S. K. 
Singh, and P. H. L. Worth, ``Does the Kaufman Prosthesis Still Have 
a Place? Review of Thirteen Years' Experience,'' Urology, 38(4):328-
331, 1991.
    102. Foley, M., M. Stefan, R. E. Campbell, and T. R. Malloy, 
``The Radiographic Evaluation of GU Prostheses,'' Applied Radiology, 
22(10):24-36, 1993.
    103. Tiemann, D., L. Shea, C. G. Klutke, K. Gaehle, and S. 
Moore, ``Artificial Urinary Sphincters. Treatment for Post-
Prostatectomy Incontinence,'' AORN Journal, 57(6):1366-1372, 1375-
1379, 1993.
    104. Diokno, A. C., J. B. Hollander, and T. P. Alderson, 
``Artificial Urinary Sphincter for Recurrent Female Urinary 
Incontinence: Indications and Results,'' The Journal of Urology, 
138(4):778-780, 1987.
    105. Herzog, A. R., A. C. Diokno, and N. H. Fultz, ``Urinary 
Incontinence: Medical and Psychosocial Aspects,'' Annual Review of 
Gerontology and Geriatrics, 9:74-119, 1989.
    106. Harty, J. I., and L. W. Howerton, Jr., ``Experience With 
the Artificial Sphincter 800 in Patients With Severe Urinary 
Incontinence,'' Journal of the Kentucky Medical Association, 
83(9):485-489, 1985.
    107. Denes, B., ``Urinary Incontinence. An Introduction,'' Trans 
American Society of Artificial Internal Organs, 34(4):998-999, 1988.
    108. Jakobsen, H., and T. Hald, ``Management of Neurogenic 
Urinary Incontinence With AMS Artificial Urinary Sphincter,'' 
Scandinavian Journal of Urology and Nephrology, 20(2):137-141, 1986.
    109. Jumper, B. M., G. A. McLorie, B. M. Churchill, A. E. 
Khoury, and A. Toi, ``Effects of the Artificial Urinary Sphincter on 
Prostatic Development and Sexual Function in Pubertal Boys With 
Meningomyelocele,'' The Journal of Urology, 144(2 pt 2):438-342; 
Discussion 443-444, 1990.
    110. Domanskis, E. J., and J. Q. Owsley, ``Histological 
Investigations of the Etiology of Capsule Contraction Following 
Augmentation Mammoplasty,'' Plastic and Reconstructive Surgery, 
58:689-693, 1976.
    111. Vargas, A., ``Shedding of Silicone Particles From Inflated 
Breast Implants,'' letter to the editor, Plastic and Reconstructive 
Surgery, 64:252-253, 1979.

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