Gastroenterology-Urology Devices; Effective Date of the Requirement for Premarket Approval of the Implanted Mechanical/ Hydraulic Urinary Continence Device

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 876

[Docket No. 94N-0380]

Gastroenterology-Urology Devices; Effective Date of the

Requirement for Premarket Approval of the Implanted Mechanical/

Hydraulic Urinary Continence Device

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; opportunity to request a change in

classification.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to require

the filing of a premarket approval application (PMA) or a notice

[[Page 8596]] of completion of a product development protocol (PDP) for

the implanted mechanical/hydraulic urinary continence device, a medical

device. The agency is also summarizing its proposed findings regarding

the degree of risk of illness or injury designed to be eliminated or

reduced by requiring the device to meet the statute's approval

requirements, and the benefits to the public from the use of the

device. In addition, FDA is announcing an opportunity for interested

persons to request that the agency change the classification of the

device based on new information.

DATES: Written comments by June 15, 1995; requests for a change in

classification by March 2, 1995. FDA intends that, if a final rule

based on this proposed rule is issued, PMA's will be required to be

submitted within 90 days of the effective date of the final rule.

ADDRESSES: Submit written comments or requests for a change in

classification to the Dockets Management Branch (HFA-305), Food and

Drug Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: John H. Baxley, or John F. Guest,

Center for Devices and Radiological Health (HFZ-470), Food and Drug

Administration, 9200 Corporate Blvd., Rockville, MD 20850, 301-594-

2194.

SUPPLEMENTARY INFORMATION:

I. Background

Section 513 of the Federal Food, Drug, and Cosmetic Act (the act)

(21 U.S.C. 360c) requires the classification of medical devices into

one of three regulatory classes: Class I (general controls), class II

(special controls), and class III (premarket approval). Generally,

devices that were on the market before May 28, 1976, the date of

enactment of the Medical Device Amendments of 1976 (the amendments)

(Pub. L. 94-295), and devices marketed on or after that date that are

substantially equivalent to such devices, have been classified by FDA.

For the sake of convenience, this preamble refers to both the devices

that were on the market before May 28, 1976, and the substantially

equivalent devices that were marketed on or after that date as

``preamendments devices.''

Section 515(b)(1) of the act (21 U.S.C. 360e(b)(1)) establishes the

requirement that a preamendments device that FDA has classified into

class III is subject to premarket approval. A preamendments class III

device may be commercially distributed without an approved PMA or

declared completed PDP until 90 days after FDA's promulgation of a

final rule requiring premarket approval for the device, or 30 months

after final classification of the device under section 513 of the act,

whichever is later. Also, a preamendments device subject to the

rulemaking procedures under section 515(b) of the act is not required

to have an approved investigational device exemption (IDE) (part 812

(21 CFR part 812)) contemporaneous with its interstate distribution

until the date identified by FDA in the final rule requiring the

submission of a PMA for the device.

Section 515(b)(2)(A) of the act provides that a proceeding to

promulgate a final rule to require premarket approval shall be

initiated by publication, in the Federal Register, of a notice of

proposed rulemaking containing: (1) The proposed rule; (2) proposed

findings with respect to the degree of risk of illness or injury

designed to be eliminated or reduced by requiring the device to have an

approved PMA or declared completed PDP and the benefit to the public

from the use of the device; (3) an opportunity for the submission of

comments on the proposed rule and the proposed findings; and (4) an

opportunity to request a change in the classification of the device

based on new information relevant to the classification of the device.

Section 515(b)(2)(B) of the act provides that if FDA receives a

request for a change in the classification of the device within 15 days

of the publication of the notice, FDA shall, within 60 days of the

publication of the notice, consult with the appropriate FDA advisory

committee and publish a notice denying the request for change of

classification or announcing its intent to initiate a proceeding to

reclassify the device under section 513(e) of the act. If FDA does not

initiate such a proceeding, section 515(b)(3) of the act provides that

FDA shall, after the close of the comment period on the proposed rule

and consideration of any comments received, promulgate a final rule to

require premarket approval, or publish a notice terminating the

proceeding. If FDA terminates the proceeding, FDA is required to

initiate reclassification of the device under section 513(e) of the

act, unless the reason for termination is that the device is a banned

device under section 516 of the act (21 U.S.C. 360f).

If a proposed rule to require premarket approval for a

preamendments device is made final, section 501(f)(2)(B) of the act (21

U.S.C. 351(f)(2)(B)) requires that a PMA or notice of completion of a

PDP for any such device be filed within 90 days of the date of

promulgation of the final rule or 30 months after final classification

of the device under section 513 of the act, whichever is later. If a

PMA or notice of completion of a PDP is not filed by the later of the

two dates, commercial distribution of the device is required to cease.

The device may, however, be distributed for investigational use if the

manufacturer, importer, or other sponsor of the device complies with

the IDE regulations. If a PMA or notice of completion of a PDP is not

filed by the later of the two dates, and no IDE is in effect, the

device is deemed to be adulterated within the meaning of section

501(f)(1)(A) of the act, and subject to seizure and condemnation under

section 304 of the act (21 U.S.C. 334) if its distribution continues.

Shipment of the device in interstate commerce will be subject to

injunction under section 302 of the act (21 U.S.C. 332), and the

individuals responsible for such shipment will be subject to

prosecution under section 303 of the act (21 U.S.C. 333). FDA has in

the past requested that manufacturers take action to prevent the

further use of devices for which no PMA or notice of completion of a

PDP has been filed and may determine that such a request is appropriate

for implanted mechanical/hydraulic urinary continence devices.

The act does not permit an extension of the 90-day period after

promulgation of a final rule within which an application or a notice is

required to be filed. The House Report on the amendments states that

``the thirty month `grace period' afforded after classification of a

device into class III * * * is sufficient time for manufacturers and

importers to develop the data and conduct the investigations necessary

to support an application for premarket approval.'' (H. Rept. 94-853,

94th Cong., 2d sess. 42 (1976).)

A. Classification of the Implanted Mechanical Hydraulic Urinary

Continence Device

In the Federal Register of November 23, 1983 (48 FR 53012 at

53026), FDA issued a final rule classifying the implanted mechanical/

hydraulic urinary continence device into class III Sec. 876.5280 (21

CFR 876.5280). The preamble to the proposal to classify the device (46

FR 7610, January 23, 1981) included the recommendation of the

Gastroenterology-Urology Devices Advisory Panel (the Panel), an FDA

advisory committee, which met on September 26 and 27, 1976, regarding

the classification of the device. The Panel recommended that the device

be in class III, and identified certain risks to health presented by

the device. FDA agreed with the Panel's [[Page 8597]] recommendation

and proposed that the implanted mechanical/hydraulic urinary continence

device be classified into class III. The proposal stated that the

agency believed that general controls and performance standards are

insufficient to provide reasonable assurances of the safety and

effectiveness of the device and that there is insufficient information

to establish a standard to provide reasonable assurances of the safety

and effectiveness of the device. The proposal stated that premarket

approval is necessary for this device because it presents a potential

unreasonable risk of injury due to: (1) Adverse tissue reaction and

erosion; (2) leakage of urine secondary to device defects; (3)

infection resulting from defects in the design, construction,

packaging, or processing of the device; (4) urinary tract infection,

secondary to urine stasis, occurring as a result of the inflation cuff

locking in the closed position; and (5) additional surgery that might

be required as a result of a malfunction of the device. In support of

its proposal to strengthen regulatory surveillance of the device, FDA

cited references supporting the proposed classification.

The preamble to the November 23, 1983, final rule (48 FR 53012)

classifying the device into class III advised that the earliest date by

which PMA's for the device could be required was June 30, 1986, or 90

days after promulgation of a rule requiring premarket approval for the

device, whichever occurs later. In the Federal Register of January 6,

1989 (54 FR 550), FDA published a notice of intent to initiate

proceedings to require premarket approval of 31 preamendments class III

devices assigned a high priority by FDA for the application of

premarket approval requirements. Among other things, the notice

described the factors FDA takes into account in establishing priorities

for proceedings under section 515(b) of the act for promulgating final

rules requiring that preamendments class III devices have approved

PMA's. Although the implanted mechanical/hydraulic urinary continence

device was not listed among these 31 devices, the agency has received

more than 2,700 medical device reports (MDR's) since 1984 for this

device. Additionally, the types of problems identified in these reports

are similar to those identified during the classification proceedings

of the device. Therefore, FDA has determined that the implanted

mechanical/hydraulic urinary continence device identified in

Sec. 876.5280 has a high priority for initiating a proceeding to

require premarket approval. Accordingly, FDA is commencing a proceeding

under section 515(b) of the act to require that the implanted

mechanical/hydraulic urinary continence device has an approved PMA or a

declared completed PDP.

B. Dates New Requirements Apply

In accordance with section 515(b) of the act, FDA is proposing to

require that a PMA or a notice of completion of a PDP be filed with the

agency for the implanted mechanical/hydraulic urinary continence device

within 90 days after promulgation of any final rule based on this

proposal. An applicant whose device was legally in commercial

distribution before May 28, 1976, or has been found by FDA to be

substantially equivalent to such a device, will be permitted to

continue marketing the implanted mechanical/hydraulic urinary

continence device during FDA's review of the PMA or notice of

completion of the PDP. FDA intends to complete the review of any PMA

for the device within 180 days and a notice of completion of a PDP

within 90 days of the date of filing. FDA cautions that, under section

515(d)(1)(B)(i) of the act, FDA may not enter into an agreement to

extend the review period for a PMA beyond 180 days unless the agency

finds that ``* * * the continued availability of the device is

necessary for the public health.''

FDA intends that, under Sec. 812.2(d), the preamble to any final

rule based on this proposal will state that, as of the date on which a

PMA or notice of completion of a PDP is required to be filed, the

exemptions in Sec. 812.2(c)(1) and (c)(2) from the requirements of the

IDE regulations for preamendments class III devices will cease to apply

to any implanted mechanical/hydraulic urinary continence device which

is: (1) Not legally on the market on or before that date, or (2)

legally on the market on or before that date but for which a PMA is not

filed by that date, or for which PMA approval has been denied or

withdrawn.

If a PMA or notice of completion of a PDP for the implanted

mechanical/hydraulic urinary continence device is not filed with FDA

within 90 days after the date of promulgation of any final rule

requiring premarket approval for the device, commercial distribution of

the device must cease. The device may be distributed for

investigational use only if the requirements of the IDE regulations

regarding significant risk devices are met. The requirements for

significant risk devices include submitting an IDE application to FDA

for its review and approval. An approved IDE is required to be in

effect before an investigation of the device may be initiated or

continued. FDA, therefore, cautions that IDE applications should be

submitted to FDA at least 30 days before the end of the 90-day period

after the final rule to avoid interrupting investigations.

C. Description of the Device

An implanted mechanical/hydraulic urinary continence device is a

device used to treat urinary incontinence by the application of

continuous or intermittent pressure to occlude the urethra. The totally

implanted device may consist of either a static pressure pad, or a

system with a container of saline or radiopaque fluid in the abdomen

and a manual pump and valve under the skin surface that is connected by

tubing to an adjustable pressure pad or to a cuff around the urethra.

The fluid is pumped as needed from the container to inflate the pad or

cuff to compress the urethra. These devices are most commonly

constructed from silicone elastomers. Additionally, static pressure pad

designs have been known to contain silicone gel and/or polyurethane

foam covering.

The proposed rule to require premarket approval of implanted

mechanical/hydraulic urinary continence devices applies to legally

marketed implanted mechanical/hydraulic urinary continence devices

identified above that were commercially distributed before May 28,

1976, and to devices introduced into commercial distribution since that

date that have been found to be substantially equivalent to such

implanted mechanical/hydraulic urinary continence devices.

D. Proposed Findings With Respect to Risks and Benefits

As required by section 515(b) of the act, FDA is publishing its

proposed findings regarding: (1) The degree of risk of illness or

injury designed to be eliminated or reduced by requiring the implanted

mechanical/hydraulic urinary continence device to have an approved PMA

or a declared completed PDP; and (2) the benefits to the public from

the use of the device.

E. Degree of Risk

After considering the information discussed by the Panel during the

classification proceedings, as well as the published literature and

MDR's, FDA has evaluated the risks associated with the implanted

mechanical/hydraulic urinary continence device. FDA now believes that

the following are [[Page 8598]] significant risks associated with the

use of the implanted mechanical/hydraulic urinary continence device:

1. Erosion of the Implanted Mechanical/Hydraulic Urinary Continence

Device

Erosion is the destruction or breakdown of tissue and is the most

common cause of failure in the implanted mechanical/hydraulic urinary

continence device (Refs. 1 through 5). Cuff erosion into the urethra or

bladder neck is a serious complication that has been frequently

reported (Refs. 3 and 6 through 15). This type of erosion makes

reimplantation difficult and is associated with higher complication

rates for reimplantation (Refs. 1 and 16 through 18) of the device.

Erosion of the pump through the labia, vagina, scrotum (Refs. 14 and 19

through 21), and the perineum (Refs. 2, 9, and 22) have also been

reported.

Erosion often occurs as a result of low grade, nonclinical

infection of the prosthesis (Refs. 9, 14, and 23 through 28). Other

factors which can contribute to erosion include previous surgery (Ref.

11), poor vascularization (Refs. 27 and 29 through 31), prior pelvic

irradiation (Refs. 17, 28, and 32 through 35), improper cuff size (Ref.

30), improper reservoir volume (Ref. 17), surgical injury (Refs. 18 and

24), excessive urethral compression (Ref. 16), and premature activation

(Refs. 19 and 27).

2. Infection

Infection, a risk of any surgical implant procedure, is associated

with the use of implanted mechanical/hydraulic urinary continence

devices (Refs. 7, 10, 12, 33, and 36 through 39). Infection is one of

the most serious potential complications of device implantation and

usually necessitates removal of the prosthesis (Refs. 7, 40, and 41).

As in any implantation procedure, compromised device sterility and/or

surgical techniques may be major contributing factors to this risk

(Refs. 40 and 42). Additionally, a life-long risk for hematogenously

seeded infection possibly exists in these patients and antibacterial

prophylaxis for subsequent dental and surgical procedures may be needed

(Ref. 40).

3. Mechanical Malfunctions

Fluid leakage is one of the most commonly reported mechanical

malfunctions (Refs. 2, 26, 28, 37, 43, and 44) of implanted mechanical/

hydraulic urinary continence devices. Fluid can leak from the cuff or

pad (Refs. 7, 13, 21, 31, and 45), reservoir (Refs. 7, 13, and 31), or

connectors (Ref. 10). Leakage from the cuff has been associated with

cuff folding and attendant material wear (Refs. 31, 36, and 46). This

malfunction results in inadequate cuff pressure and incontinence (Ref.

7). Tube kinking is another reported device malfunction (Refs. 7, 12,

26, 28, 34, 37, 43, 44, and 47). Also, disconnection of the tubing from

components of the device can occur (Ref. 19). Pump assembly failure is

another noted complication (Refs. 2, 19, 36, 37, and 44) of this

implant. This can include malfunction of the valves within the

hydraulic system (Ref. 45). Finally, balloon herniation has been noted

(Ref. 17). Device malfunction usually requires replacement or revision

surgery (Refs. 7 and 43).

4. Iatrogenic Disorders

Iatrogenic complications can occur as a result of any medical

procedure, including implantation of the implanted mechanical/hydraulic

urinary continence device. Improper device handling (including cutting

or nicking of the device) can lead to device malfunctions. Inadequate

pressure within the system (due to selection of incorrect cuff or

reservoir size) results in either incontinence (due to inadequate

urethral closing pressure) or outflow obstruction (due to excessive

urethral closing pressure), both of which lead to the need for

reoperation (Refs. 7, 12, 30, and 34). This may be due to a lack of

guidance for determining the appropriate device size for an individual

patient (Refs. 2, 9, 25, 31, and 48). Erosion secondary to infection,

can be caused by intraoperative field contamination or urethral or

vaginal injury (Refs. 26 and 42). Finally, intraoperative and

postoperative kinks in the tubing can occur due to incorrect tubing

length (Ref. 7) and result in a low urethral closure pressure (Refs. 9,

34, and 48).

5. Hydronephrosis

Hydronephrosis refers to the dilation of the upper urinary tract as

a result of chronic obstruction to urine outflow, which can lead to

kidney damage. Some authors have reported an elevated incidence of

hydronephrosis following implantation of the implanted mechanical/

hydraulic urinary continence device (Refs. 49 through 52). This

complication has mostly occurred when the device is implanted in

patients with myelopathy. It has been theorized that the development of

hydronephrosis is due to a combination of slight detrusor hyperreflexia

and low bladder capacity (Ref. 49). Other researchers have noted the

development of detrusor hypertonicity after implantation, leading to

hydronephrosis (Ref. 52). The pathogenesis and incidence of this risk

is unknown and requires further study.

6. Human Carcinogenicity

Carcinogenesis has been widely discussed as a reputed risk

secondary to implantation of any material. Evidence from the literature

indicates that in animal studies, different forms of silicone have been

associated with various types of cancer (Refs. 53 through 57). Cases of

several types of cancer in humans have been reported in association

with various forms of implanted silicone (Refs. 58 through 61).

7. Human Reproductive and Teratogenic Effects

The effect of certain silicone compounds on the reproductive

potential of the male is largely unknown. Le Vier and Jankowiak report

that at least one form of organosiloxane, which is known to be present

in some silicone gels, mimics estrogens in the male rat, leading to

rapid testicular atrophy (Ref. 62).

Teratogenesis includes the origin or mode of production of a

malformed fetus and the disturbed growth processes involved in the

production of a malformed fetus. Studies using silicone fluid in

animals have been minimal, and yield contradictory and inconclusive

results (Refs. 63 through 65). Prolonged contact with either silicone

elastomer, or silicone gel-filled membrane in devices containing

silicone gel, presents a potential risk of teratogenicity in humans.

Further study of these risks is necessary.

8. Immune Related Connective Tissue Disorders--Immunological

Sensitization

Immunological sensitization may be a serious risk associated with

an implanted mechanical/hydraulic urinary continence device. Recent

clinical data have shown that silicone elastomers are capable of

producing immune responses (Ref. 66). Immune related connective tissue

disorders have also been reported in women who have silicone gel-filled

devices or who have had silicone injections in augmentation

mammoplasty. There are clinical reports of several patients who have

undergone augmentation mammoplasty with silicone gel-filled breast

prostheses and later presented with connective tissue disease-like

syndromes (Ref. 67). Recently, Naim et. al. conducted studies in rats

which demonstrated that silicone gel is a potent immunological adjuvant

(Ref. 68). Because implanted mechanical/hydraulic urinary continence

devices may consist of similar silicone elastomers and gels,

[[Page 8599]] further study of the potential risk of immune related

connective tissue disorders in humans with these implants is warranted.

9. Biological Effects of Silica

Amorphous (fumed) silica is bound to the silicone in the elastomer

of the implanted mechanical/hydraulic urinary continence device, and

may be fibrogenic and immunogenic. Fumed silica and the silicone

elastomer each elicit cellular responses in rats (Ref. 69). Researchers

have reported that there is an association between industrial exposure

to silica and development of systemic lupus erythematosus (Ref. 41).

The biological effects of silica, particularly the immunologic

component of these reactions, present a potential risk for device

recipients and need to be examined.

10. Silicone Particle Shedding, Silicone Gel Leakage, and Associated

Migration

Silicone particle shedding and subsequent migration have been

reported with genitourinary prosthetic devices, including implanted

mechanical/hydraulic urinary continence devices (Refs. 70 and 71).

Silicone gel leakage and migration from the silicone elastomer

envelope, either from rupture of the envelope or by leaking of the gel

through the envelope (gel ``bleed''), are also potential significant

risks of implanted mechanical/hydraulic urinary continence devices

containing silicone gel. Rupture of the envelope with gel leakage and

subsequent migration may be secondary to surgical technique, or may

result from mechanical stresses such as device usage, trauma, and wear

on the envelope, and necessitates removal of the implant. In addition,

silicone gel-filled breast implants are reported to ``bleed'' micro

amounts of silicone through the intact silicone elastomer shell into

the surrounding tissues (Refs. 72 through 81). Furthermore,

fluorosilicone gels have been used to lubricate the inner surfaces of

cuff shells (Ref. 36) and, therefore, are an additional source for gel

bleed. Although diffusion of silicone gel through the elastomer

envelope and silicone particle shedding have not specifically been

measured (e.g., quantified) in the implanted mechanical/hydraulic

urinary continence device, they have been reported (Ref. 70) and,

therefore, particle shedding and gel bleed continue to be potential

risks with this device and need to be evaluated. Migration of the

particles and gel into the human body presents the potential for

development of adverse effects such as granulomas, lymphadenopathy, or

cellular immune response (Refs. 41, 58, 59, 70, and 71). The ultimate

fate of migrating silicone particles or silicone gel within the body is

currently not well understood. It should be noted that the use of

silicone gel in these devices may have been discontinued.

11. Degradation of Polyurethane Elastomer

Polyurethane elastomer materials, which may be present in some

implanted mechanical/hydraulic urinary continence devices, may degrade

over time and release degradation products such as methylene diamine or

toluene diamine, which are potential carcinogens in animals (Refs. 82

and 83). FDA is not aware of any mechanical/hydraulic urinary

incontinence devices which currently use this material. This potential

risk is associated only with those implanted mechanical/hydraulic

urinary continence devices that contain polyurethane elastomers.

12. Degradation of Polyurethane Foam

This potential risk is associated only with those implanted

mechanical/hydraulic urinary continence devices that are covered with

polyurethane foam. The polyurethane foam material that has been used to

cover some devices is known to degrade over time with a potential

breakdown product of 2,4 diaminotoluene (TDA), a known carcinogen in

animals (Refs. 84 through 89). The fate of the degraded product in vivo

is unknown to date, and the use of this material in implanted

mechanical/hydraulic urinary continence devices may have been

discontinued. Case reports of polyurethane foam covered silicone gel-

filled breast implants indicate that there is greater difficulty with

the removal of this type of prosthesis due to fragmented polyurethane

shell and/or capsular tissue ingrowth (Refs. 90 through 96). Also,

foreign body response has been reported concurrent with the use of the

polyurethane foam covered testicular prosthesis in humans (Ref. 97).

13. Other Reported Complications

The following are among the additional risks which have also been

reported with the implanted mechanical/hydraulic urinary continence

device: perineal discomfort/pain (Refs. 10, 17, and 27); development of

bladder hyperreflexia (Refs. 98 through 100); worsening/persistence of

incontinence (Refs. 51, 99, and 100); urinary retention (Refs. 51 and

101); hematoma (Ref. 28); seroma (Ref. 44); inguinal hernia formation

(Ref. 102); fibrous capsule formation, failure of cuff to deflate,

broken tubing (Ref. 51); fistula formation from urethral erosion (Ref.

8); urethral scarring (Ref. 99); bleeding (Ref. 103); urethral

stricture requiring urethrotomy (Ref. 101); wound dehiscence, pelvic

abscess (Ref. 104); and fistula to the skin (Ref. 10).

F. Benefits of the Device

The implanted mechanical/hydraulic urinary continence device is

intended to provide intermittent or continuous pressure to occlude the

urethra, thereby restoring urinary continence. The device is indicated

in males or females whose urinary sphincter is dysfunctional.

Implants have been used to treat incontinence resulting from

prostatectomy, myelopathy (e.g., spina bifida, myelomeningocele),

spinal column injury, sacral agenesis/ dysgenesis, exstrophy/epispadias

syndrome, pelvic trauma, and other conditions.

Although there are adverse physiologic effects associated with

urinary incontinence (e.g., infection and skin irritation due to

exposure to urine) (Ref. 105), the incontinent patient's mental health

and quality of life can also suffer significantly. Incontinence can be

socially, psychologically, and physically debilitating (Refs. 43 and

106). A reduction of social activities and interactions can be

associated with the loss of urinary continence (Ref. 105). The loss of

self-esteem (Ref. 107) and emotional problems (Ref. 25) have also been

associated with this condition. Finally, some research has shown a

relationship between depression indices and incontinence (Ref. 105).

An implanted mechanical/hydraulic urinary continence device can

restore continence and may improve quality of life. Published studies

indicate a moderately high success rate for either restoring or

improving continence. Some of these studies have also noted that the

restoration of continence can improve quality of life (Refs. 20 and 38)

and self-esteem (Ref. 26).

G. Need for Information for Risk/Benefits Assessment of the Device

As the above sections indicate, there is reasonable identification

of the risks and benefits associated with the implanted mechanical/

hydraulic urinary continence device. There is, however, insufficient

valid scientific evidence to permit FDA to perform a risk/benefit

analysis. Therefore, FDA is now seeking further information on the

following safety and effectiveness issues associated with the implanted

mechanical/hydraulic urinary continence device: [[Page 8600]]

(1) Long-term safety and effectiveness data for the device are

needed. The incidence of implant failure and attendant causes, as well

as the incidence of reoperations required, have not been clearly

determined. Such device failures include, but are not limited to:

Tissue erosion, infection, pain/discomfort, injury to the upper urinary

tract due to either urinary retention or hydronephrosis, continued or

worsened incontinence secondary to implantation of the implanted

mechanical/hydraulic continence device, leakage, wear, tubing kinking/

breaking or disconnection, pump failure, and cuff or pad failure. Also,

the incidence rates of hematoma, seroma, inguinal hernia formation,

fibrous capsule formation, fistula formation from urethral erosion,

urethral scarring, bleeding, urethral stricture, development of bladder

hyperreflexia, wound dehiscence, pelvic abscess, and fistula to the

skin are poorly understood and need to be studied. Particularly, it is

not well known whether the increased urethral resistance afforded by

implanted mechanical/hydraulic urinary continence devices eventually

leads to chronic upper urinary tract damage (e.g., hydronephrosis and/

or worsening of renal function). This risk is especially a concern for

young patients, who are most likely to have the device in place for

many years.

(2) It is unknown for which subgroups of the population with

urinary incontinence the benefits of the implanted mechanical/hydraulic

continence device outweigh the attendant risks, especially since other

voiding abnormalities, such as bladder dysfunction (detrusor

instability and poor compliance) and reflux often coexist with

sphincteric insufficiency. Factors which may increase the rate of

complications include the etiology and duration of incontinence, age,

gender, concomitant medical conditions, various anatomical

abnormalities, patient motivation and manual dexterity, and prior

treatments for the disorder, including prior surgery. An appropriate

risk/benefit analysis is needed for each subgroup for whom the device

will be indicated.

(3) The required presurgical workup of patients prior to device

implantation, including the diagnostic tests to demonstrate significant

sphincteric insufficiency which could be treated with the prosthesis,

must be clarified. In particular, the proper patient selection and

screening processes need to be developed and studied. Since some

adverse events, such as persistent urinary incontinence, may be

associated with other coexisting urodynamic abnormalities (e.g.,

bladder dysfunction), these abnormalities must be effectively diagnosed

prior to device implantation (Refs. 7, 22, and 108). The increased risk

of hydronephrosis among device recipients whose bladders are unable to

store urine at low pressures underscores the importance of thorough

preoperative patient evaluation with special attention to bladder

function and urodynamics (Ref. 103). Additionally, because the adverse

events that may occur following implantation of the device may not be

reversible, investigation is needed to determine which prior

conservative therapies a patient should have failed before being

considered an appropriate candidate for an implanted mechanical/

hydraulic continence device.

(4) The long-term effects of devices implanted in pediatric

patients need to be investigated. Currently, the relationship between

patient growth and the need for implanted mechanical/hydraulic

continence device revision or replacement is poorly understood and

warrants further study. While some researchers report no effects

related to the growth of the child, others report the potential for an

effect upon both the growth/morphology of the organs in the urinary

tract, as well as sexual development and function in children (Refs. 24

and 109).

(5) The effects of the implanted mechanical/hydraulic continence

device upon male sexual function are poorly understood. In particular,

the effect of the device upon erectile function needs to be examined.

(6) Since women of childbearing age are among the recipients of

implanted mechanical/hydraulic continence devices, the effects of the

device upon sexual function, pregnancy, and delivery must be analyzed.

(7) The effect of device implantation upon future medical diagnoses

and treatments needs to be examined. Currently, it is not well

understood whether the device's presence interferes with the ability to

diagnose and treat disorders affecting the organs or structures in

proximity to the implant components.

(8) The potential risks associated with silicone particle shedding

and silicone gel leakage, and the subsequent migration of the particles

and gel, need further clarification. This would include consideration

of gel cohesiveness, envelope thickness/strength, gel bleed, and the

role that the physical, mechanical, and chemical characteristics of

silicone elastomers and gels play in the immediate or long-term wear of

implanted mechanical/hydraulic urinary continence devices. (The

agency's concerns regarding silicone gel relate specifically to devices

with gel-filled components, such as certain models of the implanted

static pressure pad.)

(9) The potential long-term adverse effects of implanted

mechanical/hydraulic urinary continence devices, such as cancer, immune

related connective tissue disorders, and reproductive and teratogenic

effects, are unknown. Likewise, in polyurethane elastomer and/or

polyurethane foam covered implanted mechanical/hydraulic urinary

continence devices (known to be applicable to certain models of the

implanted static pressure pad), the long-term effects of the

polyurethane material (such as mechanical integrity and

carcinogenicity) are not understood. The agency notes that neither the

silicone particles, which may shed from the device (Refs. 70, 110, and

111), nor the chemical forms of silicone monomers and oligomers, or

additives (including catalysts, antioxidants, fillers, reinforcers, and

other processing agents), which may leach from the device, have been

characterized, and their metabolic fates are not known (Ref. 64).

Furthermore, no satisfactory independent study has thoroughly evaluated

the chronic long-term toxicity of silicone elastomers and their

derivatives. Because children are among the potential recipients of

these implants, information regarding the chronic toxic effects,

including possible reproductive and teratogenic effects, of silicone

could be of substantial importance in determining the risk to these

patients and their offspring.

(10) The malfunction rate and longevity reported for implanted

mechanical/hydraulic urinary continence devices have generally not

reflected the predictions of preclinical testing. Further investigation

is warranted to determine how the laboratory and animal studies can be

designed to more accurately predict device reliability under actual

conditions of use.

FDA believes, therefore, that the implanted mechanical/hydraulic

urinary continence device should undergo premarket approval to obtain

valid scientific evidence in order for FDA to determine whether the

risks of using the device are adequately balanced by its benefits.

II. PMA Requirements

Any PMA for the device must include the information required by

section 515(c)(1) of the act and the implementing provisions under 21

CFR 814.20. Such a PMA shall include a [[Page 8601]] detailed

discussion, accompanied by the results of applicable preclinical and

clinical studies, of the above identified risks and the effectiveness

of the device. In particular, the PMA shall include all known or

otherwise available data and other information regarding: (1) Any risks

known or should be reasonably known to the applicant that have not been

identified in this document; and (2) the effectiveness of the specific

implanted mechanical/hydraulic urinary continence device that is the

subject of the application.

Valid scientific evidence, as defined in Sec. 860.7 (21 CFR 860.7),

addressing the safety and effectiveness of the device should be

presented, evaluated and summarized in a section or sections of the PMA

separate from known or otherwise available safety and effectiveness

information that does not constitute valid scientific evidence (e.g.,

isolated case reports, random experiences, etc.).

A. Manufacturing Information

All manufacturing information for the device should be completely

described. The information should include but, is not necessarily

limited to, the chemical formulation and manufacturing procedures and

processes, presented in a step-by-step manner from the starting

materials to the finished product, including, but not limited to, all

nonreactants (such as antioxidants, light stabilizers, plasticizers,

i.e., anything added to polymer resins that is necessary for processing

of the finished product) and reactants (including catalysts, curing

agents, and intermediate precursors) for the pad (including

polyurethane foam covering, if applicable), cuff, pump, reservoir,

tubing, and all internal components, adhesives, colorants, lubricants,

and filling agents (e.g., gel, saline, contrast medium, etc.). A

complete master list of the common chemical names and alternate names

(manufacturer's trade name or code) for all nonreactants, reactants

(including intermediate precursors), additives, catalysts, adjuvants,

and products should be provided.

Chemical characterization of the elastomer intermediates (i.e.,

network precursors) of the pad (including polyurethane foam covering,

if applicable), cuff, pump, reservoir, tubing, and internal gel (if

applicable) sufficient to demonstrate control of the chemical

processing of the device materials should be provided. This should be

based on lot-to-lot comparisons (10 consecutive lot minimum) of the

following information: (1) The molecular weight distribution, expressed

as weight average molecular weight, number average molecular weight,

peak molecular weight, polydispersity, and viscosity average molecular

weight of these precursors; (2) analyses for volatile and nonvolatile

(if applicable) compounds, such as cyclic oligomers; (3) when viscosity

is used as the variable that is measured for production control, a

comparison of viscosity, number average molecular weight, and volatile

content; and (4) isocyanate content, acidity, isomer ratios, hydroxyl

number, water content, acid number, and peroxide content (where

applicable). Documentation establishing the extent of cross-linking

(where applicable) in the materials of the pad, cuff, pump, reservoir,

tubing, and all internal components and filling agents, or the

silicone-hydride and vinyl content of cross-linked materials of the

pad, cuff, pump, reservoir, tubing, and all internal components and

filling agents, as well as the particle size and surface area of the

silica if present in the pad, cuff, pump, reservoir, tubing, and the

composition of all internal components, filling agents, or gel should

be provided. A complete description of the medium used to inflate the

device (saline, contrast medium, etc.) and whether and how the implant

will be prefilled must also be provided.

The standard operating procedures for sterility and materials

qualifications must be provided. Sterilization information should

include the method of sterilization; the detailed sterilization

validation protocol and results; the sterility assurance level; the

type of packaging; the packaging validation protocol and results;

residual levels of ethylene oxide, ethylene glycol, and ethylene

chlorohydrin remaining on the device after the sterilization quarantine

period, if applicable; and the radiation dose, if applicable.

A complete description of the functional testing of subassemblies

and finished products performed during the manufacturing process and

during quality assurance/quality control (QA/QC) testing must be

provided. Functional testing performed during manufacturing and QA/QC

procedures should detect any device flaws that could lead to short-term

failure and should demonstrate functional integrity of the device. A

QA/QC plan that demonstrates how raw materials, components,

subassemblies, and any filling agents will be received, stored, and

handled in a manner designed to prevent damage, mixup, contamination,

and other adverse effects must be provided. This plan shall

specifically include, but not necessarily be limited to, a record of

raw material, component, subassembly, and filling agent acceptance and

rejection, visual examination for damage, and inspection, sampling and

testing for conformance to specifications.

Written procedures for finished device inspection to assure that

device specifications are met must be provided. These procedures shall

include, but are not limited to, the requirement that each production

run, lot or batch be evaluated and, where necessary, tested for

conformance with device specifications prior to release for

distribution. A representative number of samples shall be selected from

a production run, lot or batch and tested under simulated use

conditions and to any extremes to which the device may be exposed.

Furthermore, the QA/QC procedures must include appropriate visual

testing of the packaging, packaging seal, and product. Sampling plans

for checking, testing, and release of the device shall be based on an

acceptable statistical rationale (21 CFR 820.80 and 820.160).

B. Preclinical Data

Complete identification and quantification of all chemicals,

including residual amine containing components, volatile and

nonvolatile silicone cyclics and oligomers below a molecular weight of

1,500 exhaustively extracted from each of the individual structural

components (pad, cuff, pump, reservoir, tubing, and any other

materials, lubricants, or filling agents) as they are found in the

final sterilized device should be reported. The solvents used for

extraction should have varying polarities and should include, but not

be limited to, ethanol/saline (1:9) and dichloromethane. Other, more

contemporary extraction techniques, such as supercritical fluid

extraction, may also be useful, at least for exhaustive extraction of

the silicone materials. Experimental evidence must be provided

establishing that exhaustive extraction is achieved with one of the

selected solvents, and the percent recovery, especially for the more

volatile components, must be reported. Extracts that may contain

oligomeric or polymeric species must have the molecular weight

distribution provided along with the number and weight average

molecular weight, and polydispersity. All experimental methodologies

must be described, and raw data (including instrument reports) must be

provided along with all chromatographs, spectrograms, etc. The limit of

detection (two times noise level) must be provided when the analyte of

interest is not detected. Laboratory test methods and animal

experiments used [[Page 8602]] in the characterization of the physical,

chemical (other than exhaustive extraction) and mechanical properties

of the device should be applicable to the intended use of the device in

humans. Infrared measurements of the surface of device components as

they occur in the final, sterilized product should be provided.

Biocompatibility testing data must be provided for all materials

(pad, cuff, pump, reservoir, tubing, filling agents, gels, lubricants,

and any other materials) in the implanted mechanical/hydraulic urinary

continence device, including all color additives (ink, dyes, markings,

etc.) used to fabricate the implanted mechanical/hydraulic urinary

continence device. FDA guidance on biocompatibility testing is

available in the document titled ``Tripartite Biocompatibility Guidance

for Medical Devices.'' A copy may be obtained upon request from the

Division of Small Manufacturers Assistance (HFZ-220), Center for

Devices and Radiological Health, Food and Drug Administration, 5600

Fishers Lane, Rockville, MD 20857. Biocompatibility evaluation should

follow the methodology of tests for tissue contacting, long-term

internal devices.

Toxicological effects (e.g., cytotoxicity, mutagenicity, affects on

the immune system, and reproductive and developmental toxicity) should

be identified. Complete mutagenicity testing of extracts from the

finished, sterilized components of the device should be provided. These

tests should include the following: Bacterial mutagenicity, mammalian

mutagenicity, deoxyribonucleic acid (DNA) damage, and cell

transformation assay.

Acute, subchronic, and chronic toxicity studies using the chemicals

recovered by the above exhaustive extraction processes should be

provided in the evaluation of the long-term biocompatibility of the

device, including dose response and time to response as well as gross

and histopathological findings in tissues both surrounding implants and

distal to implant sites (lymph nodes, prostate, urethra, bladder,

ovaries/testes, liver, kidneys, lungs, uterus, etc.). Animal studies of

carcinogenicity, reproductive toxicity, teratogenicity, and later

effects on offspring must be performed using scientifically justified

test methods. These studies must include animal testing of the extracts

from the final sterilized device. Teratology/ reproductive testing of

the final sterilized device and extractables should be performed in an

appropriate species using validated methods. Furthermore, for those

devices that contain silicone gel, a subset of these studies must test

the compounds extracted from the materials of the sterilized device for

estrogen-like antigonadotropic activity in an appropriate animal model

using scientifically valid methods.

Pharmacokinetic/biodegradation studies of all materials contained

in the finished device should state all materials of toxicological

concern, such as amine, silicone, and fluorosilicone compounds. Of

special concern are questions regarding the ultimate fate, quantities,

sites/organs of deposition, routes of excretion, and potential clinical

significance of silicone shedding, retention, and migration. Data on

the distribution and metabolic fate of amine containing components,

silicone, and any other materials used in the manufacturing of the

device should be supplied.

Animal testing should also be conducted to study the effect of

implantation upon device function and material integrity. Complete

device chemical characterization and mechanical testing should be

performed after devices have been implanted in an appropriate animal

model for an appropriate length of time. Of special concern is the

material integrity of the pad, cuff, reservoir, pump, tubing, joints,

etc., which should be functionally tested and investigated using

electron microscopy. The results of this testing should be compared to

the failure rates noted during in vitro testing and clinical studies in

order to demonstrate that the animal model and study duration chosen

are appropriate.

For the implanted mechanical/hydraulic urinary continence device

designs that contain silicone gel, or employ a silicone gel as a

lubricant, the gel bleed performance of the device, as determined from

the results of measurements using a standard diffusion cell maintained

at a temperature simulating physiologic conditions using stirred,

physiologic saline as a receptacle medium for the bleed, must be

reported. Each variation in thickness or device design must be measured

to accurately determine diffusion coefficients (with appropriate time

dependencies). The chemical identification of the bleed product,

including, but not limited to, amine containing components, volatile

and nonvolatile silicone cyclics and oligomers below a molecular weight

of 1,500 and molecular weight distribution, must be reported.

For the polyurethane covered designs (foam or elastomer), FDA

believes that in vivo implant studies must be performed to identify and

determine the bioabsorption, distribution, and elimination of the

polyurethane covering (as well as their degradation products) in

experimental animals. It is also important to identify and determine

the mechanism and rate of degradation, as well as the quantity of TDA

or other products generated by the breakdown of polyurethane covered

implanted mechanical/hydraulic urinary continence devices after

prolonged exposure under physical conditions in animals. Additionally,

the agency recommends that retrospective epidemiological and

prospective clinical studies be designed to assess the potential of

cancer and other long-term complications related to implanted

mechanical/hydraulic urinary continence devices containing

polyurethane. The agency suggests that these preclinical and

epidemiological studies be conducted as a separate subset of implanted

mechanical/hydraulic urinary continence device safety studies.

In vitro testing should be conducted at the component, subassembly,

and final device levels and must examine all aspects of device design,

construction, and operation. This testing should also demonstrate how

the device design and manufacturing processes address the failure mode

and effects analysis. The failure mode effects analysis should be

provided. Copies of the original data sheets from all tests must be

included in the PMA. All device failures must be completely described,

and the corrective actions taken to eliminate or minimize further

recurrence should also be identified.

An adequate number of samples of each model, based on relevant

power calculations, will be required. If marketing approval is sought

for multiple device versions, each version requires its own set of

preclinical tests and results. If sample devices of each available size

are not tested, it must be clearly indicated which device sizes were

used for each test. The absence of testing on each size must be

justified by analysis demonstrating that the results from the tested

devices will accurately predict results for the untested device sizes.

The test conditions and acceptance criteria for all tests should be

completely explained and justified. All tests should be performed on

final, sterilized devices in an environment simulating the possible

range of anticipated in vivo conditions (temperatures, pressures,

forces, stresses, etc.), where possible. All methods used to determine

the condition of the device after testing, e.g., visual examination,

electrical [[Page 8603]] continuity, electron microscope examination,

functional testing, etc., must be discussed and justified.

All data collected from in vitro and animal testing, regarding the

useful lifetime or long-term reliability of the device, must be

compared to data from clinical studies (prospective and/or

retrospective) where the useful lifetime of the device has been

determined. This comparison must validate the ability of the in vitro

and animal tests to accurately predict the useful lifetime of the

implanted device.

If accelerated aging is used to demonstrate device durability and

reliability, all processes used should be completely described, and the

calculations validating the expected aging should be provided.

All physical, chemical, and functional properties of the device

should be completely characterized, and the design specifications must

be adequately justified. Chemical characterization should include,

where applicable, molecular weight and molecular weight distribution,

cross-link density, infrared analysis (free isocyanate content, side

reaction products), and differential scanning calorimetry. The physical

tests should include, but are not necessarily limited to the tests

discussed below.

Testing should include the following specific methods or their

equivalents: (1) American Society for Testing Materials (ASTM) Test

Method D412 to measure tensile strength, force to breakage, ultimate

elongation, and total energy to rupture of the pad, cuff, pump,

reservoir, tubing, and bulk of all elastomeric components (with and

without incorporated fold flaws) of the finished, sterilized device;

dynamic mechanical analysis and fatigue characterization of all

elastomeric components particularly those comprising the cuff of the

finished, sterilized device; (2) ASTM Test Method D624 to determine

tear and abrasion resistance of all components; an applied force at the

rate of 1 Hertz versus number of cycles to failure (AF/N) curve

(including the minimum force required to rupture the component under a

single stroke of applied load), constructed on the basis of cyclical

compression testing of intact sterilized devices; and (3) ASTM Test

Method F703 (section 7.2) to determine the force to break of adhered or

fused joints. A complete report of the cohesivity and penetration

testing of the gel must also be reported for the devices containing

silicone gel. The results of each of these tests must be compared to

the energy, forces, etc., that the device will encounter in vivo.

Life testing should demonstrate the device is sufficiently durable

to withstand the demands of use while maintaining operational

characteristics sufficient for urethral compression throughout the

expected operational lifetime of the implanted mechanical/hydraulic

urinary continence device, as stated in the physician and patient

labeling. Life testing should include measurements of all component and

material wear and bond strengths after the device is cycled between

inflated and deflated conditions. A discussion comparing the rate of

cycling performed in each test to the approximate maximum rate of

cycling of the device in vivo and to the expected longevity of the

implant should be included.

Appropriate ``downtimes'' at predetermined cyclical intervals

should be included in the life tests to evaluate relevant performance

characteristics and conformance to design specifications. Material

characteristics indicative of material degradation that could induce

device malfunction should be completely evaluated. Cyclical testing

beyond the expected longevity of the implant and recording of failure

mode must also be included as part of the life tests.

Filling agent permeability from the reservoir and body of the

device must be evaluated to demonstrate that fluid loss due to osmosis

will be acceptable over the expected life of the implanted mechanical/

hydraulic urinary continence device.

Component-specific tests are also necessary. Reliability over the

expected life of the device, proper operation, and conformance to

predetermined operational specifications must be demonstrated for each

component. Resistance of each component to abrasion, tear, crazing,

fracture, material fatigue (including wear between each component),

change of position (e.g., valve seats), and permanent deformation also

must be demonstrated.

Pad characterization and testing should include, but not be limited

to: Measurement of stiffness and rigidity, including resistance to

buckling; uniformity of dimensions (if the device is inflated); and

wear characteristics.

Cuff characterization and testing should include, but not be

limited to: Maximum pressure and expansion capability; measurement of

stiffness, including resistance to buckling; resistance to aneurysms;

ability of cuff closure to remain inflated under maximum loads expected

in vivo; uniformity of inflated dimensions; inflation and deflation

characteristics; and wear characteristics at folds in the cuff.

Pump characterization and testing should include, but not be

limited to: The range of volumes displaced per stroke; minimum force

required to affect fluid displacement; squeeze force versus fluid

displacement; inflation effort, defined as pump force times the number

of strokes required for full device activation; and ability of the

implanted mechanical/hydraulic urinary continence device to maintain

its set pressure after repeated punctures to its pressure adjustment

port with both new devices and devices evaluated in the reliability

tests.

Valve characterization and testing should include, but not be

limited to: Pump output pressure required to affect valve opening for

device activation; tactile pressure/force required to affect valve

opening, against fully inflated cuffs, for deflation; back pressure

required for valve failure; maximum pressure differential across closed

valve at full inflation and deflation, and the leakage rates at these

pressures; prevention of spontaneous deflation under movements and

loads simulating those expected to be sustained by the implanted device

in an inflated state; and potential for valve failure which could

result in an inability to inflate or deflate the cuff.

Reservoir characteristics should be evaluated and should include,

but not be limited to: Volume capacity; pressures generated over the

inflation/deflation cycle; rate of maximum fluid outflow and inflow;

wear characteristics if a fold in the reservoir envelope occurs; and

durability tests demonstrating adequate resistance to fatigue caused by

cyclic external compression applied radially to inflated reservoir.

Tubing testing should include, but not be limited to: Tensile

characteristics (with and without tubing connectors, if any); tear or

rupture resistance; kink resistance; wear characteristics if a fold in

the tubing develops; and ability of the tubing to remain intact under

loads simulating and exceeding those expected in vivo.

Testing to demonstrate the inflation/deflation characteristics of

the device should include, but not be limited to: Amount of pressure

generated during inflation of the cuff; amount of pressure drop

(deflation) and rise (inflation) per unit time; ability to maintain the

inflated cuff dimensions; and time to fully inflate and deflate the

cuff from specified starting pressures.

All bonds within the device and between components should undergo

appropriate testing including, but not be limited to measurement of

bond shear and tensile strength. Bond strength [[Page 8604]] should

exceed the loads expected during device handling and after

implantation.

Other components of the implanted mechanical/hydraulic urinary

continence device or accessories, such as tubing connectors, extension

adapters, and specialized tools used during the insertion procedure,

should be evaluated appropriately. Testing of these components or

accessories should reflect the anticipated conditions of use; for

example, tubing connectors should be demonstrated to be able to

maintain connection to the device for the expected life of the device.

C. Clinical Data

Valid scientific evidence, as defined in Sec. 860.7(c)(2), which

includes information from well-controlled investigations, partially

controlled studies, studies and objective trials without matched

controls, well-documented case histories conducted by qualified experts

and reports of significant human experience with a marketed device from

which it can fairly and responsibly be concluded by qualified experts

that there are reasonable assurances of the safety and effectiveness of

the implanted mechanical/hydraulic urinary continence device. Detailed

protocols for the clinical trials, with explicit patient inclusion/

exclusion criteria and well-defined followup schedules, should be

specified. FDA believes that 5-year followup data are necessary in

order to characterize the safety and effectiveness of the device over

its expected lifetime; however, appropriately justified alternate

followup schedules will be considered. Any deviations from the protocol

should be stated and justified. Time-course presentations of

restoration of continence (dryness) or significant improvement in

continence, as well as other information on the anatomical and

physiological effects of the implanted mechanical/hydraulic urinary

continence device (including all adverse events) should be provided.

Full patient accounting should be reported, including: (1) Theoretical

followup (the number of patients that would have been examined if all

patients were examined according to their followup schedules); (2)

patients lost to followup, excluding deaths, should include measures

taken to minimize such events (with all available information obtained

on patients lost to followup) and should not exceed 20 percent over the

course of the study; (3) time course of revisions, including all

explant and repair data; and (4) time-course of deaths (stating the

cause of death, including the reports from any postmortem

examinations). As part of this patient accounting, each clinical report

should clearly state the date that the data base was closed to the

addition of new information. Detailed patient demographic analyses and

characterizations should be presented to show that the patients

enrolled in the study are representative of the population for whom the

device is intended.

A statistical demonstration, based on the number of patients who

complete the required study period, should show that the sample size of

the clinical study is adequate to provide accurate measures of the

safety and effectiveness of this device. The statistical demonstration

should identify the effect criteria, clinically reasonable levels for

Type I (alpha) and Type II (beta) errors, and anticipated variances of

the response variables. The statistical demonstration should also

provide any assumptions made and all statistical formulas used (with

copies of any references). A complete description of all patient

randomization techniques used, and how these techniques were employed

to exclude potential sources of bias, should be provided. Statistical

justifications for pooling across several demographic or surgical

variables, such as the etiology and duration of incontinence, age,

gender, concomitant medical conditions, various anatomical

abnormalities, the type or model of the device implanted, the number

and type of treatments (if any) attempted to restore continence prior

to device implantation, device usage (initial implantation versus

revision), investigational site, degree of patient motivation and

manual dexterity, surgeon experience and technique, and pad or cuff

placement site, should be provided. The data collected and reported

should include all necessary variables in order to permit

stratification and analysis of the study data required to evaluate the

risk/benefit ratio for each clinically relevant subpopulation of

patients.

Appropriate concurrent control/comparison groups should be included

and justified and, if not, their absence must be justified. All

hypotheses to be tested must be clearly stated. Appropriate statistical

techniques must be employed to test these hypotheses as support for

claims of safety and effectiveness. For each relevant subgroup, a

sufficient number of patients need to be followed for a sufficient

length of time to support all claims (explicit and implied) in any PMA

submission.

To evaluate the risks to the patient from the implanted mechanical/

hydraulic urinary continence device, clinical studies should include

time-course presentations of clinical data demonstrating the presence

or absence of tissue erosion, infection, pain/discomfort, injury to the

upper urinary tract due to either urinary retention or hydronephrosis,

continued or worsened incontinence, leakage, wear, tubing kinking/

breaking or disconnection, pump failure, cuff or pad failure, hematoma,

seroma, inguinal hernia formation, fibrous capsule formation, fistula

formation from urethral erosion, urethral scarring, bleeding, urethral

stricture, development of bladder hyperreflexia, reoperation, wound

dehiscence, pelvic abscess, and fistula to the skin, including any

effects on the immune system (both local to the device and systemic)

and the reproductive system, without regard to the device relatedness

of the event. The diagnostic criteria for each type of immunological

and allergic phenomenon should be defined at the beginning of the

study, and all cases should be well-documented utilizing these

criteria. Patients must be regularly monitored for the occurrence of

such adverse events for a minimum of 5 years post-implantation, or

until physical maturity of the subject (whichever occurs later).

The effectiveness of the device may be assessed by an objective and

standardized recording/measurement of: (1) The ability of the device in

vivo to either restore or significantly improve urinary continence; and

(2) the enhancement of a patient's quality of life following

implantation of the device; both of which should be balanced against

any risk of illness or injury from use of the device. FDA understands

that evaluation of the degree of benefit involves, in part, an

assessment of patient quality of life, which relates to the

postoperative function of the device. Such evaluation includes

subjective factors and relates to patient expectations. Assessments of

the in vivo performance of the device's function, on the other hand,

should provide some objective measure of device effectiveness.

Documentation of the anatomical and physiologic outcomes of

implantation of an implanted mechanical/hydraulic urinary continence

device shall include:

(1) Regular postsurgical evaluations of the functional (i.e.,

inflation and deflation) characteristics of the device for at least 5

years postimplantation, or until physical maturity of the subject

(whichever occurs later);

(2) Periodic postsurgical urodynamic testing (such as measurements

of leak point pressure and the volume of urine leaked into a pad after

a standard set of [[Page 8605]] maneuvers) during this followup period,

with comparisons to baseline measurements;

(3) Regular postsurgical assessments of incontinence grade

(possibly obtained from patient voiding diaries or the number of pads

required per day to keep dry), as compared to baseline values; and

(4) Patient assessments of the mechanical function of the implant

(such as ease of activation) during this followup period (which may be

influenced by the manual dexterity or motivation of the patient).

Documentation of the effect of the device upon the patient's

quality of life shall include:

(1) Prospective research designs, including pre- and postsurgical

repeated measures for at least 5 years postimplantation, or until

physical maturity of the subject (whichever occurs later);

(2) Standardized test questions rather than informal, yet-validated

questionnaires; and

(3) Comparisons of the postsurgical scores to those measured prior

to device implantation.

Any PMA for the implanted mechanical/hydraulic urinary continence

device should separately analyze the degree of device safety and

effectiveness by the following variables: (1) Etiology; (2) duration

and degree of urinary incontinence; (3) the device type or model

implanted; (4) gender; and (5) age. Furthermore, for each explantation

procedure performed on the study subjects, the following information

must be provided: (1) The mode of failure of the removed device; (2)

whether or not the explanted device was replaced with a new device; and

(3) either the manufacturer, type and model of the new device implanted

(if another implanted mechanical/hydraulic urinary continence device

was implanted), or the type of treatment (if any) that the patient

received for his/her incontinence (if revision surgery was not

performed). Additionally, the effect of the presence of these implants

upon future medical diagnoses/treatments involving the lower pelvic

region in recipients of implanted mechanical/hydraulic urinary

continence devices must be analyzed. Furthermore, any accessories sold

with the implanted mechanical/hydraulic urinary continence device must

be shown to have been effectively used in implant procedures without

adverse effects. Finally, each clinical investigation should validate

the physician and patient instructions for use (labeling) that were

used, particularly the instructions regarding the selection of the

appropriate device size (if applicable).

For polyurethane foam covered implants, the following additional

information needs to be presented:

(1) The kinetics of end products generated from the degradation of

the polyurethane material (in vivo);

(2) The frequency and incidence of infection and complication of

retrieval of the implant by surgeons; and

(3) The neoplasticity of these materials and products, as well as

their general toxicity, including neurological, physiological,

biochemical, and hematological effects, as well as pathology following

prolonged and repeated exposure to polyurethane foam covered implanted

mechanical/hydraulic urinary continence devices.

Any epidemiological studies submitted should contain sufficient

subjects to permit detection of a small, but clinically significant,

increase in one or more connective tissue diseases (especially

scleroderma) that may be associated with the use of the device.

The agency believes that insufficient time has elapsed to permit a

direct evaluation of the risks of cancer and immune related connective

tissue disorders posed by the presence of silicone in the human body,

and that insufficient epidemiological and experimental animal data are

available to make a reasonable and fair judgment of these risks.

Furthermore, the potential long-term risk of hydronephrosis and/or

decreases in renal function in patients implanted with the implanted

mechanical/hydraulic urinary continence device, due to the chronic

elevation of urethral resistance experienced postimplantation, has yet

to be quantified and is a concern of the agency. Therefore, the agency

will require long-term postapproval followup for any implanted

mechanical/hydraulic urinary continence device permitted in commercial

distribution. Well-designed clinical prospective studies with long-term

followup together with experimental animal studies will be considered

essential to the determination of the safety and effectiveness of the

device. Further, these clinical studies must collect long-term data on

the reproductive/teratogenic effects of the device as well as on the

later effects on the offspring.

The risk/benefit assessment (as with the entire PMA) must rely on

valid scientific evidence as defined in Sec. 860.7(c)(2) from well-

controlled studies as described in Sec. 860.7(f) in order to provide

reasonable assurance of the safety and effectiveness of the implanted

mechanical/hydraulic continence device in the treatment of urinary

incontinence.

D. Labeling

Copies of all proposed labeling for the device including any

information, literature, or advertising that constitutes labeling under

section 201(m) of the act (21 U.S.C. 321(m)), should be provided. The

general labeling requirements for medical devices are contained in 21

CFR part 801. These regulations specify the minimum requirements for

all devices. Additional guidance regarding device labeling can be

obtained from FDA's publication ``Labeling: Regulatory Requirements for

Medical Devices,'' and from the Office of Device Evaluation's ``Device

Labeling Guidance''; both documents are available upon request from the

Division of Small Manufacturers Assistance (address above). Highlighted

below is additional guidance for some of the specific labeling

requirements for implanted mechanical/hydraulic urinary continence

devices.

The intended use statement should include the specific indications

for use and identification of the target populations. Specific

indications and target populations must be completely supported by the

clinical data described above. For example, it may be necessary to

restrict the intended use to patients who have failed prior less

invasive therapies and/or to patients with specific etiologies of

incontinence in whom safety and effectiveness have been demonstrated.

The directions for use should contain comprehensive instructions

regarding the preoperative, perioperative, and postoperative procedures

to be followed. This information includes, but is not necessarily

limited to: (1) A description of any preimplant training necessary for

the surgical team; (2) a description of how to prepare the patient

(e.g., prophylactic antibiotics), operating room (e.g., what supplies

must be on hand), and implanted mechanical/hydraulic urinary continence

device (e.g., handling instructions, resterilization instructions) for

device implantation; (3) instructions for implantation, including

possible surgical approaches, sizing, fluid adjustment (including what

filling solutions may be used and how they must be prepared), device

handling, and intraoperative test procedures to ensure implant

functionality and proper placement; and (4) instructions for followup,

including whether antibiotic prophylaxis is recommended during the

postimplant period and/or during any subsequent dental or other

surgical procedures, how to determine when [[Page 8606]] patients are

ready to activate the device, and how to evaluate, and how often to

evaluate, proper functionality and placement. The directions should

instruct caregivers to specifically question patients prior to surgery

for any history of allergic reaction to any of the device materials or

filling agents. Troubleshooting procedures should be completely

described. The directions for use should incorporate the clinical

experience with the implant, and should be consistent with those

provided in other company-provided labeling.

The labeling should include both implant and explant forms to allow

the sponsor to adequately monitor device experience. The explant form

should allow collection of all relevant data, including the reason for

the explant, any complications experienced and their resolution, and

any action planned (e.g., replacement with another implant).

Patient labeling must be provided which includes the information

needed to give prospective patients realistic expectations of the

benefits and risks of device implantation. Such information should be

written and formatted so as to be easily read and understood by most

patients and should be provided to patients prior to scheduling

implantation, so that each patient has sufficient time to review the

information and discuss it with his or her physician(s). Technical

terms should be kept to a minimum and should be defined if they must be

used. Patient information labeling should not exceed the seventh grade

reading comprehension level.

The patient labeling should provide the patient with the following

information: (1) The indications for use and relevant

contraindications, warnings, precautions and adverse effects/

complications should be described using terminology well known and

understood by the average layman; (2) the anticipated benefits and

risks associated with the device must be provided to give patients

realistic expectations of device performance and potential

complications. The known, suspected and potential risks of device

implantation should be identified and the consequences, including

possible methods of resolution, should be described; (3) alternatives

available to the use of the device, including less invasive treatments,

should be identified, along with a description of the associated

benefits and risks of each. The patient should be advised to contact

his physician for more information on which of these alternatives might

be appropriate given his specific condition; (4) instructions for how

to use the device must be provided to the patient. This information

should include the expected length of recovery from surgery and when to

attempt activation following implantation, whether and how often the

device should be periodically cycled (if applicable), warnings against

certain actions that could damage the device, how to identify

conditions that require physician intervention, who to contact if

questions arise, and other relevant information; (5) the fact that the

implant should not be considered a ``lifetime'' implant must be

emphasized. Where possible, the patient labeling should provide

information on the approximate number of revisions necessary for the

average patient, and indicate the average longevity of each implant so

patients are fully aware that additional surgery for device

modification, replacement, or removal may be necessary. This

information must be supported by the clinical experience (i.e., not

merely bench studies) with the implant or by published reports of

experience with similar devices.

The physician's labeling should instruct the urologist or

implanting surgeon to provide the implant candidate with the patient

labeling prior to surgery to allow each patient sufficient time to

review and discuss this information with his physician(s).

The adequacy and appropriateness of the instructions for use

provided to physicians and patients should be verified as part of the

clinical investigations.

Applicants should submit any PMA in accordance with FDA's

``Premarket Approval (PMA) Manual.'' The manual is available upon

request from the Division of Small Manufacturers Assistance (address

above).

III. Comments

Interested persons may, on or before June 15, 1995, submit to the

Dockets Management Branch (HFA-305), Food and Drug Administration, rm.

1-23, 12420 Parklawn Dr., Rockville, MD 20857, written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

between 9 a.m. and 4 p.m., Monday through Friday.

Those wishing to make comments are encouraged to discuss all

aspects of the proposed findings regarding the following topics:

(1) Degree of risk, illness, or injury associated with the use of

the implanted mechanical/hydraulic urinary continence device;

(2) Laboratory, animal, and human studies required in a PMA for the

device in order to assess its safety and effectiveness;

(3) Feasibility of these studies within the time permitted by the

act, etc.; and

(4) Benefits to the public from the use of the device.

The comments must discuss in detail, for example, the reasons why

important new information on the safety and effectiveness of the device

could not feasibly be submitted within the time permitted, or why

animal studies may not be available to assess long-term effects such as

connective tissue disorders, or that carefully designed epidemiological

studies may not be available to evaluate the long-term silicone related

illnesses, etc.

The Center for Devices and Radiological Health staff are available

to provide guidance to manufacturers on any proposed laboratory,

animal, or epidemiological studies needed in a PMA.

IV. Opportunity to Request a Change in Classification

Before requiring the filing of a PMA or a notice of completion of a

PDP for a device, FDA is required by section 515(b)(2)(A)(i) through

(b)(2)(A)(iv) of the act and 21 CFR 860.132 to provide an opportunity

for interested persons to request a change in the classification of the

device based on new information relevant to its classification. Any

proceeding to reclassify the device will be under the authority of

section 513(e) of the act.

A request for a change in the classification of the implanted

mechanical/hydraulic urinary continence device is to be in the form of

a reclassification petition containing the information required by

Sec. 860.123 (21 CFR 860.123), including new information relevant to

the classification of the device, and shall, under section 515(b)(2)(B)

of the act, be submitted by March 2, 1995.

The agency advises that to assure timely filing of any such

petition, any request should be submitted to the Dockets Management

Branch (address above) and not to the address provided in

Sec. 860.123(b)(1). If a timely request for a change in the

classification of the implanted mechanical/hydraulic urinary continence

device is submitted, the agency will, by April 17, 1995, after

consultation with the appropriate FDA advisory committee and by an

order published in the Federal Register, either deny the request or

give notice of its intent to initiate a change in the

[[Page 8607]] classification of the device in accordance with section

513(e) of the act and 21 CFR 860.130.

V. References

The following references have been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday through Friday.

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3. Herschorn, S., and S. B. Radomski, ``Fascial Slings and

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4. Malloy, T. R., A. J. Wein, and V. L. Carpiniello, ``Surgical

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33(4)274-276, 1989.

5. Riemenschneider, H. W., and S. G. Moon, ``Experience in

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Sphincter,'' Ohio State Medical Journal, 79(8):630-633, 1983.

6. Aaronson, I. A., ``The AS 800 Artificial Urinary Sphincter in

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69(11):686-688, 1986.

7. Barrett, D. M., and B. G. Parulkar, ``The Artificial

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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

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13(2):122-125, 1991.

9. Lowe, D. H., H. C. Scherz, and C. L. Parsons, ``Urethral

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Urology, 31(1):82-85, 1988.

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1983.

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Patients,'' Urology, 35(3):215-218, 1990.

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Sphincters,'' British Journal of Hospital Medicine, 47(8):591-596,

1992.

29. Goldwasser, B., W. L. Furlow, and D. M. Barrett, ``The Model

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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

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1464, 1992.

48. Lorentzen, T., S. Dorph, and T. Hald, ``Artificial Urinary

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1987.

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50. Light, J. K., and T. Pietro, ``Alteration in Detrusor

Behavior and the Effect on Renal [[Page 8608]] Function Following

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51. Medical Device Reporting (MDR) and Product Problem Reporting

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52. Roth, D. R., P. R. Vyas, R. L. Kroovand, and A. D.

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57. Pedley, R. B., G. Meachim, and D. F. Williams, ``Tumor

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58. Benjamin, E., A. Ahmed, A. T. M. F. Rashid, and D. H.

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59. Digby, J. M., and A. L. Welles, ``Malignant Lymphoma With

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60. Morgenstern, L., S. H. Gleischman, S. L. Michel, J. E.

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61. Zafiracopoulos, P., and A. Rouskas, ``Breast Cancer at Site

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62. Le Vier, R. R., and M. E. Jankowiak, ``Effects of Oral 2,6-

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VI. Environmental Impact

The agency has determined under 21 CFR 25.24(a)(8) that this action

is of a type that does not individually or cumulatively have a

significant effect on the human environment. Therefore, neither an

environmental assessment nor an environmental impact statement is

required.

VII. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impacts; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the proposed

rule is not a significant regulatory action as defined by the Executive

Order and so is not subject to review under the Executive Order.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. Because PMA's for this device could have been

required by FDA as early as June 30, 1986, and because firms that

distributed this device prior to May 28, 1976, or whose device has been

found by FDA to be substantially equivalent will be permitted to

continue marketing the implanted mechanical/hydraulic urinary

continence device during FDA's review of the PMA or notice of

completion of the PDP, the agency certifies that the proposed rule will

not have a significant economic impact on a substantial number of small

entities. Therefore, under the Regulatory Flexibility Act, no further

analysis is required.

List of Subjects in 21 CFR Part 876

Medical devices.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR part 876 be amended as follows:

PART 876--GASTROENTEROLOGY-UROLOGY DEVICES

1. The authority citation for 21 CFR part 876 continues to read as

follows:

Authority: Secs. 501, 510, 513, 515, 520, 701 of the Federal

Food, Drug, and Cosmetic Act (21 U.S.C. 351, 360, 360c, 360e, 360j,

371).

2. Section 876.5280 is amended by revising paragraph (c) to read as

follows:

Sec. 876.5280 Implanted mechanical/hydraulic urinary continence

device.

* * * * *

(c) Date PMA or notice of completion of a PDP is required. A PMA or

notice of completion of a PDP is required to be filed with the FDA on

or before (insert date 90 days after the effective date of a final rule

based on this proposed rule), for any implanted mechanical/hydraulic

urinary continence device that was in commercial distribution before

May 28, 1976, or that has on or before (insert date 90 days after the

effective date of a final rule based on this proposed rule), been found

to be substantially equivalent to the implanted mechanical/hydraulic

urinary continence device that was in commercial distribution before

May 28, 1976. Any other implanted mechanical/hydraulic urinary

continence device shall have an approved PMA or declared completed PDP

in effect before being placed in commercial distribution.

Dated: January 10, 1995.

D.B. Burlington,

Director, Center for Devices and Radiological Health.

[FR Doc. 95-3805 Filed 2-14-95; 8:45 am]

BILLING CODE 4160-01-F