SUMMARY OF SAFETY AND EFFECTIVENESS

# I. GENERAL INFORMATION

### **Device Generic Name**: Implanted Mechanical/Hydraulic Urinary Continence Device 

**Device Trade Name**: AMS Sphincter 800™ Urinary Prosthesis

**Applicant's Name and Address**: American Medical Systems

10700 Bren Road West

Minnetonka, MN 55343

**PMA Number**: P000053

**Date of Notice of Approval to Applicant**: June 14, 2001

# II. INDICATIONS FOR USE

The AMS Sphincter 800™ Urinary Prosthesis is used to treat urinary
incontinence due to reduced outlet resistance (Intrinsic Sphincter
Deficiency).

# III. DEVICE DESCRIPTION

The AMS Sphincter 800™ Urinary Prosthesis is a small fluid-filled device
that is implanted within the body. The device is implanted in men who
developed urinary incontinence due to reduced outflow resistance
(intrinsic sphincter deficiency, ISD) following prostate surgery. It is
designed to restore the natural process of urinary control. The device
simulates normal sphincter function by opening and closing the urethra
at the control of the patient. The device is made primarily from solid
silicone elastomer and consists of three components: a cuff, a pump, and
a pressure-regulating balloon (Figure 1). The components are filled with
either normal saline or contrast media and are connected to each other
with kink-resistant tubing and Suture-Tie or Quick Connect (sutureless)
connectors The device is assembled intraoperatively by the surgeon using
1 of 12 different cuff lengths, a control pump, and 1 of 5 different
pressure regulating balloons. The cuff lengths vary from 4.0 cm to 11.0
cm, and the balloon pressures range from 41 cm H~2~O to 90 cm H~2~O
(41-50, 51-60, 61-70, 71-80, 81-90 cm H~2~O). The surgeon selects the
suitable cuff length by using a cuff sizer with gradations around the
urethra.

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height="4.9319444444444445in"}

**Figure 1. AMS Sphincter 800™ Urinary Prosthesis**

**Device Operation**

The cuff has an inner shell and outer backing. The inner shell expands
when filled with fluid. The cuff is implanted at the bulbous urethra in
males. The pump is implanted in the scrotum and the pressure-regulating
balloon is implanted in the abdomen. Pressure regulating balloons are
designed to maintain cuff pressure within one of 5 narrow pressure
ranges, regardless of the volume of fluid emptying or filling that
occurs during prosthesis use. The upper part of the pump contains a
resistor and valves to transfer fluid to and from the cuff. The lower
part of the pump forms a bulb that helps in emptying the bladder. The
cuff occludes the bladder neck or urethra by applying gentle pressure
around the circumference of the anatomical structure. When the patient
wishes to void, he gently squeezes the lower part of the control pump
several times. This moves fluid that pressurizes the cuff into the
control pump and then on into the pressure-regulating balloon. As fluid
leaves the cuff, it deflates and the urethra opens, enabling the patient
to void. The fluid resistor in the pump then automatically allows
gradual refilling of the cuff by transferring fluid from the balloon.
Within several minutes, the cuff refills and again closes the urethra.

IV. **CONTRAINDICATIONS**

    This device is contraindicated in patients whom the physician
    determines to be poor candidates for surgical procedures and/or
    anesthesia due to physical or mental conditions.

    This device is contraindicated in patients with urinary incontinence
    due to or complicated by an **irreversibly** obstructed lower
    urinary tract.

This device is contraindicated in patients with irresolvable detrusor
hyperreflexia or bladder instability.

V.  **WARNINGS AND PRECAUTIONS**

> **Warnings**

1.  Patients with urinary tract infections, diabetes, spinal cord
    injuries, open sores, or skin infections in the region of the
    surgery have an increased risk of infection associated with the
    prosthesis. Appropriate measures should be taken to reduce the
    likelihood of infection. Infection that fails to respond to
    antibiotic therapy may result in removal of the prosthesis.
    Infection followed by explanation of the device may result in
    scarring which may make subsequent reimplantation more difficult.

2.  Erosion may be caused by infection pressure on the tissue, improper
    cuff sizing, improper balloon selection, tissue damage, and
    component replacement. The cuff may erode around the urethra or
    bladder neck, or the control pump may erode through the scrotum. The
    pressure-regulating balloon can erode into the bladder. Acute
    urinary tract infection can interfere with proper functioning of the
    device and may lead to erosion of the urethra in the cuff area.
    Failure to evaluate and promptly treat the erosion may result in
    substantial worsening of the condition leading to infection and/or
    loss of tissue.

3.  Poor bladder compliance or a small fibrotic bladder may require some
    measure of intervention including, in some cases, augmentation
    cystoplasty before implanting the prosthesis.

4.  Patients with urge incontinence, overflow incontinence, detrusor
    hyperreflexia or bladder instability should have these conditions
    treated and controlled (or resolved) prior to implantation of the
    device.

5.  Do not pass a catheter or any other instrument through the urethra
    without first deflating the cuff and deactivating the device.

6.  This device contains solid silicone elastomers. This device does not
    contain silicone gel. The risks and benefits of implanting this
    device in patients with documented sensitivity to silicone should be
    carefully considered.

7.  Surgical, physical, psychological, or mechanical complications, if
    they occur, they may necessitate revision or removal of the
    prosthesis. Removal of the device without timely reimplantation of a
    new device may complicate subsequent reimplantation. The timing of
    reimplantation should be determined by the treating physician based
    on the patient's medical condition and history.

8.  Product wear, component disconnection or other mechanical problems
    may lead to surgical intervention. Mechanical complications may
    include malfunctioning of the components and leakage of fluid. Any
    mechanical malfunction that does not permit the transfer of fluid
    from the cuff to the balloon may result in overflow obstruction.
    Mechanical events should be evaluated carefully by the treating
    physician, and the patient should consider the benefits and risks of
    treatment options, including revision surgery.

9.  Previous patient history of adverse reaction to radiopaque solution
    precludes its use as a filling medium for the prosthesis. Instead
    saline should be used to fill the device.

**Precautions**

## Patient Related

1.  Patient selection requires thorough preoperative consultation and
    evaluation by the physician.

2.  Patients should be counseled in order to have a realistic
    expectation of the physical, psychological, and functional outcome
    of the implantation of the prosthesis. Although the prosthesis is
    designed to restore urinary control some patients continue to have a
    degree of incontinence after this procedure.

3.  Patients may experience pain when the device is activated in the
    postoperative period and during periods of initial use. Cases of
    chronic pain associated with the device have been reported. Pain
    with a severity or duration beyond that which is expected may
    require medical or surgical intervention. Patients should be
    counseled on expected postoperative course of pain including
    severity and duration.

4.  Tissue fibrosis, previous surgery, or radiation therapy in the area
    of the implant may preclude implantation of the cuff at the bulbous
    urethra or bladder neck.

5.  Any progressively degenerative disease, e.g. multiple sclerosis, may
    limit the future usefulness of the implanted prosthesis as a
    treatment of the patient\'s urinary incontinence.

6.  Adequate manual dexterity, strength, and motivation are required for
    proper use of the device.

7.  Trauma or injury to the pelvic, perineal or abdominal areas, such as
    impact injuries associated with sports, can result in damage to the
    implanted device and/or surrounding tissues. This damage may result
    in the malfunction of the device and may necessitate surgical
    correction including replacement of the prosthesis. The physician
    should advise patients of these possibilities and warn them to avoid
    trauma to these areas.

## Surgery Related

1.  Improper cuff sizing, improper balloon selection, or other causes
    may result in tissue erosion, migration of components, or continued
    incontinence.

2.  Component migration can occur if the cuff is sized improperly, if
    the pump or balloon is not positioned correctly, or if the tubing
    length is incorrect. Migration can result in pain, complications,
    device malfunction and surgical revision.

.

3.  Unsuccessful outcomes may result from improper surgical technique,
    improper sterile technique, anatomical misplacement of components,
    improper sizing and/or filling of components.

4.  Although reinforced tubing has been designed to be more resistant to
    tubing kinks, tubing kinks may still result from tailoring the
    connecting tubing to an improper length during the implant
    procedure.

## Device Related

1.  If the deactivation valve is closed when the cuff is inflated, fluid
    cannot transfer from the cuff to the balloon and sustained outflow
    obstruction may arise as a result:

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a.  In the event of large pressures within the bladder, automatic
    pressure relief that normally occurs with the device would be
    prevented. Cycling the device can relieve the outflow obstruction.

b.  Cycling the device may be difficult if deactivation occurs when the
    pump bulb is deflated. If unable to cycle the prosthesis, squeezing
    the sides adjacent to the deactivation button will allow fluid to
    fill the pump bulb and then the pump can be cycled normally.

c.  Releasing the deactivation valve may require greater pressure than
    normally used to cycle the device.

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2.  Pressure changes may occur over time if you fill the balloon with
    radiopaque solution of incorrect concentration. Follow the
    instructions in the Operator's Manual to prepare the radiopaque
    solution with the correct concentration.

### **ALTERNATIVE PRACTICES AND TREATMENTS**

> Alternative treatments for stress urinary incontinence due to
> intrinsic sphincter deficiency include absorbent pads, behavioral
> techniques, drug therapy, and surgical procedures. Behavioral
> techniques have proven successful at treating mild cases of stress
> urinary incontinence (SUI). Drug therapy, including estrogen therapy
> in women, also produces successful results at treating mild cases of
> SUI. In more severe forms of SUI amenable to surgical repair, surgical
> treatments have proven successful. Injectable bulking agents and sling
> procedures are the two main types of surgery indicated for SUI due to
> ISD.

### **MARKETING HISTORY**

> The applicant submitted this application in response to the final rule
> published in the Federal Register of September 26, 2000 (Volume 65,
> No. 187, pages 57726-57732) requiring the submission of a PMA
> application for Implanted Mechanical/Hydraulic Urinary Continence
> Device. The AMS Sphincter 800 Urinary Prosthesis was cleared for
> marketing as a preamendments Class III device through the premarket
> notification (510(k)) process in 1983. FDA has cleared several
> premarket notifications for design modifications to the device since
> its introduction. A CE-mark for the AMS Sphincter 800™ Urinary
> Prosthesis was received in June 1997. AMS estimates that more than
> 45,000 AMS Sphincter 800™ Urinary Prosthesis devices have been
> implanted in patients in over 50 countries worldwide and reports that
> it has not been withdrawn from any markets for any reason related to
> safety or lack of effectiveness.

VI. **POTENTIAL ADVERSE EFFECTS OF THE DEVICE**

> A total of 43 adverse events in 26 patients were reported to be device
> related in a prospective clinical study. The various device- related
> adverse events are shown in Table 1 below. Additional details
> regarding these device-related adverse events and details regarding
> non-device related adverse events are provided later under "Clinical
> Studies-Prospective Study".

Table 1. Device Related Adverse Events in Prospective Study

Event Category Total Events No. of Patients

Compromised Device function 7 6

Pain/discomfort 6 5

Delayed Wound Healing 5 5

Migration 3 3

Recurrent Incontinence 3 3

Bladder Spasms 2 2

Difficult Activation 2 2

Tissue Erosion 2 2

Infection 2 2

Swelling 2 2

Fistula Formation 1 1

Hematoma 1 1

Hydrocele 1 1

Tissue Erosion/Infection 1 1

Patient Dissatisfaction 1 1

Positional Incontinence 1 1

Wound Infection 1 1

Urinary Retention 1 1

Difficult Deactivation 1 1

# IX. SUMMARY OF PRECLINICAL STUDIES

######### 

## A. Materials and Characterization

The materials in the AMS Sphincter 800™ Urinary Prosthesis are
predominantly solid silicone elastomers. All the elastomers are
platinum-catalyzed, solid silicones. No silicone gel was used in the
fabrication of this device. Many of the materials used are the same as
the materials used in AMS 700 Series Inflatable Penile Prosthesis
Product Line (D970012) (hereafter referred to as AMS 700 Series Penile
Prosthes). However, some silicone elastomers not used in the fabrication
of the penile prostheses are also used in the construction of the
balloon shell, cuff shell and fabric reinforced cuff backing of AMS
Sphincter 800 Urinary Prosthesis. The various safety tests described
later under "Biocompatibility Testing" specify which tests were
conducted on the new materials and which were conducted on penile
implants and included in this PMA. Furthermore, the safety of these new
materials was evaluated by chemical characterization of the
saline/ethanol (9:1) and acetone extracts and by *in vitro* and *in
vivo* biocompatibility tests conducted on the balloon and cuff
components of AMS Sphincter 800 Urinary Prosthesis. These results show
that the materials used in the fabrication of these components were not
toxic. The extraction studies and material characterization studies were
performed on finished, sterile devices.

**Chemical characterization** of the acetone extracts of the balloon and
belt cuff showed that the amounts of small molecular weight components
(Molecular Weight \<1500, D1-D18) in the extracts were in the same range
as the amounts found in AMS Malleable 650 and Dynaflex Penile
Prostheses. The amounts extracted by saline/ethanol (9:1) solvent were
at least 10-fold smaller than the amounts extracted by acetone.

**Exhuastive extraction** of the AMS Sphincter 800™ Urinary Prosthesis
device with methylene chloride and saline/ethanol ((9:1) and
characterization of the extracts followed FDA's Draft Guidance for the
preparation of PMA application for the Implanted Mechanical/Hydraulic
Urinary Continence Device (Artificial Sphincter), May 1, 1995. The
results showed that the total amount of silicone extracted in methylene
chloride was about 10% of the weight of the device and the low molecular
weight silicones (MW \<1500) accounted for 25% of the total silicone
extracted. Small amounts of Platinum (\< 2.2 μg/device), tin (\< 17
μg/device) and soluble silica (1.9 mg silicon/device in saline/ethanol
extract) were also found in these extracts. The information available in
the published literature on these chemicals and the toxicological
testing referenced below indicate health risk from these extractable
components. As would be expected, the total amount of silicone extracted
by a polar solvent such as saline/ethanol was far smaller than the
amount extracted by a nonpolar solvent such as methylene chloride.

**Infrared Spectra-ATR-FTIR** (Attenuated Fourier Transform
Spectroscopy) analysis showed that the material in the outer surface of
each device component having direct tissue contact is polydimethyl
siloxane. The surface composition is identical to the bulk composition
found in all silicone components. No other materials were detected.

**B. Biocompatibility Testing**

A battery of *in vitro* and *in vivo* tests were performed to supplement
the evidence for safety of the materials obtained from chemical analysis
of the device extracts. In these tests cells or whole organisms were
exposed to the device extracts or device materials from sterile finished
prostheses. The test program followed FDA\'s *Guidance for Manufacturers
of Silicone Devices Affected by Withdrawal of Dow Corning Silastic
Materials (July 6, 1993), and FDA's Blue Book Memorandum #G95-1,
entitled "Use of international Standard ISO-10993, Biological Evaluation
of Medical Devices, Part 1: Evaluation and Testing"*. Finished, sterile
products were subjected to the complete spectrum of biological tests
cited in the Blue Book Memorandum guidance. The majority studies
included testing of polar (saline/ethanol) and nonpolar (methylene
chloride or acetone) extracts of the device and/or device components.
The following tests were conducted on the AMS Sphincter 800 Urinary
Prosthesis (balloon and belted cuff) or the device extracts:

-   Cytotoxicity (L929 mouse fibroblasts)

-   Acute Systemic Toxicity

-   Intracutaneous Irritation

-   Sensitization in Guinea Pig (Magnusson-Kligman Maximization Study)

-   Ames Mutagenicty Test

-   Mouse Lymphoma Test

-   Mouse Micronucleus Test

-   Muscle Implantation Test (14-day and 90-day implantation in rabbits)

To provide the worst case scenario of the biocompatibility of silicone
elastomers used in the fabrication of the pressure regulating balloon,
cuff shell and cuff backing, the above tests were conducted acetone
extracts were chosen for testing since acetone is known to extracts more
silicone than saline/ethanol solvent. No evidence of cytoxicity,
mutagenic effects or significant irritation or toxicity was found in
these tests.

Since several silicone elastomers used in the AMS 700 Series Penile
Prostheses (D 970012) are also used in AMS Sphincter 800 Urinary
Prosthesis, the following studies performed on penile implant devices
were included in the PMA to further document the biocompatibility of AMS
Sphincter 800™ Urinary Prosthesis. In these studies substantial amounts
of ground silicone elastomer from finished, steam sterilized, penile
implant device were implanted subcutaneously in Sprague Dawley male
rats. The same 2-year study in the rats provided information on the fate
of the implanted material and its effect on host systems (e.g.,
toxicity, carcinogenicity) as outlined below. The studies included:

-   An Acute Pharmacokinetic Study (4-day Study) ,

-   Chronic Toxicity Study

-   Studies on Reproductive effects, and

-   Carcinogenicity Study

-   Silicone Migration Study (in Rats)

The acute pharmacokinetic study provided no evidence for transport,
excretion or tissue accumulation of implant-derived silicon compounds
during the four days following the implantation of the silicone
elastomer.

The results from the 2-year rat study showed no evidence of carcinogenic
or reproductive effects. Assays of ten distant organs (e.g., kidneys,
lungs, liver, brain, spleen, spinal cord, testes, urinary bladder,
auxiliary and inguinal lymph nodes) showed that silicon concentrations
in these organs from silicone elastomer implanted animals were not
significantly different (statistically indistinguishable) from the
levels in control animals at 6, 12, or 24 months post-implantation,
indicating that silicone or silica did not migrate from the device and
accumulate in tissues.

In addition to these studies, a separate immunological study was
conducted in male rats. This study was divided into two parts: adjuvant
effects study and immunomodulation study. In the adjuvant effects study,
the test material (ground silicone elastomer mixed with sodium
hyaluronate in phosphate buffered saline) was mixed with a known antigen
(bovine serum albumin, BSA) and injected at the same site
intramuscularly. In the immunomodulation study, the test material was
injected several times over several weeks subcutaneously, followed by a
single intramuscular injection of BSA after the last injection of the
test material. Its objective was to examine whether silicone elastomer
can serve as an adjuvant to potentiate the response to a known antigen
and whether it can produce systemic effects on the immune system such
that the response to the antigen is altered. These studies showed that
silicone elastomer did not produce a measurable enhancement of antibody
response (no adjuvant effect) or an alteration of antibody response to
BSA (immunomodulation effect).

**Conclusions from Biocompatibility Studies**

Results from all tests supported the conclusion that the materials used
in the AMS Sphincter 800™ Urinary Prosthesis do not produce local or
systemic effects and do not constitute a significant health risk to the
implanted with the device.

######### C. MECHANICAL TESTING 

A risk analysis, including failure modes and effects analysis (FMEA),
was performed to identify the safety and reliability attributes
applicable to the AMS Sphincter 800™ Urinary Prosthesis. Appropriate
cuff sizes and balloon ranges were tested to evaluate the full range of
configurations. Both non-aged and accelerated aged (5 years) samples
were tested, using both ethylene oxide sterilized and steam sterilized
samples. In all tests, sufficient number of samples were tested to
permit meaningful statistical analysis.

**Performance Testing**

Performance of the device was evaluated by testing the device and its
components for the following performance characteristics:

-   Pump squeeze force versus fluid displacement

-   Fluid displacement per pump stroke

-   Deflation effort, number of pump strokes required for cuff dilation
    and cuff deactivation time

-   Prevention of spontaneous deflation

-   Pump output pressure produced by pump squeeze force

-   Pump refill time

-   Pump deactivation force and activation pressure

-   Pump valve leakage, maximum valve back pressure and check valve
    activation pressure

-   Cuff deflation/inflation characteristics

-   Balloon deflation/inflation characteristics, maximum volume

-   Spontaneous deflation

-   Kink resistance tubing performance

-   Balloon capacity

-   Cuff expansion and maximum pressure

These tests demonstrated that the performance of the device and its
components meet the specifications and clinical requirements of the
device. The test results also indicated that device performance was not
affected by the sterilization method or accelerated aging.

**Reliability Testing**

Device reliability was evaluated by either subjecting samples to
representative *in-vivo* conditions, or to a number of estimated uses
likely to exceed the number of uses the actual use of the device.
Performance attributes evaluated include:

-   Cuff deflation/inflation reliability life cycling

-   Control pump deflation/inflation reliability life cycling

-   Balloon inflation/deflation reliability life cycling

-   Connector/kink resistant tubing connection

-   Cuff fold wear resistance reliability life cycling

-   Tubing/component adhesive bond reliability

Reliability testing demonstrated that the device and its components
exceeded the simulated use conditions equivalent to 10 years.

**Component Strength Testing**

Device strength testing was conducted in a manner similar to reliability
testing. These tests include:

-   Maximum cuff pressure, pressure to unbuckle

-   Cuff leakage or unbuckling under pressure

-   Connector/kink resistant tubing strength

-   Kink resistant tubing burst/leak pressure

-   Connector/kink resistant tubing leak pressure

-   Subassembly adhesive bond strength

-   Prosthesis material strength

Component strength testing demonstrated acceptable prosthesis or
component performance over the estimated use conditions

**D. Shelf Life Testing**

A shelf life of 5 years is claimed for the AMS Sphincter 800™ Urinary
Prosthesis. This shelf life is based on both accelerated aging studies
for sterility, packaging and performance (functionality) as well as real
time studies for packaging integrity and performance. Since the
packaging system is the same for the currently marketed AMS 700 Series
Penile Prostheses (D970012), Acticon Neosphincter (H990003) and AMS
Sphincter 800 Urinary Prosthesis, and since this system is known to
maintain the device sterility and functionality from the history of
marketing thousands of devices for 10 years, validation of accelerated
aging studies on sterility with real time studies are not considered
necessary. The accelerated aging showed that the packaging configuration
would provide physical protection and sterile barrier for a 5-year shelf
life with a 2-year margin.

**X. CLINICAL STUDIES**

Three clinical studies, all conducted by American Medical Systems, are
described in the PMA to document the safety and effectiveness of the AMS
Sphincter 800™ Urinary Prosthesis. These are referred to as the
Prospective Study, the PIF (Patient Information Form) study, and the
Retrospective Study. The Prospective Study is the smallest and the PIF
Study, the largest study. All the 3 clinical studies were conducted on
male patients. In addition, the PMA contains summaries of data presented
in numerous published articles.

**[Prospective Study]{.underline}**

The main objective of the Prospective Study was to validate the 5-year
revision free rate of 75% (within 10% variability) estimated in the PIF
Study. borrowing data from the PIF Study and using Bayesian statistics.
Since the device is a preamendment device and is not subject to IDE
regulations, the Prospective Study was a non-IDE study. In addition,
since the Prospective Study had only 2-year follow up, the 5-year
revision free rate of 75% was calculated by borrowing 90% of the data
from the PIF study and using Bayesian statistics.

**Study Design**

The Prospective Study was conducted as a multi-center, non-randomized
clinical study to demonstrate that the AMS Sphincter 800™ Urinary
Prosthesis can be surgically implanted without serious adverse sequelae
to provide an acceptable level of continence and thereby, improve the
quality of life of the patients implanted with AMS Sphincter 800
Urinary Prosthesis. The pre-implant experience of the patients served as
the control for the evaluation of effectiveness. Safety data related to
adverse events, surgical revisions, diagnoses and health status
evaluations were captured on case report forms. Patient
self-administered evaluations related to quality of life, health status,
and continence status (references provided later in the Endpoints
Section). In addition, patient and physician assessments of continence
were measured on a recognized, standardized instrument. The cut off date
for the data submitted in the PMA was October 4, 2000.

**Patient Selection**

Only male patients were eligible for enrollment in the study. The
following selection criteria were used for enrollment.

**Inclusion Criteria:**

1.  Patient has decided to be implanted with an AMS Sphincter 800™
    Urinary Prosthesis for the treatment of urinary incontinence.

2.  Patient had confirmed urinary incontinence for a minimum of 6 months
    with the primary etiology being Post-Transuethral Resection (TUR),
    Transurethral Resection of the Prostrate (TURP), or Radical
    Prostatectomy.

3.  Patient was willing and able to give informed consent.

4.  Patient was willing to return for follow-up evaluations and
    questionnaire completion.

5.  Patient was given information pertaining to alternative therapies
    available for the treatment or management of urinary incontinence
    and was informed of all possible risks related to implantation of a
    urinary prosthesis.

6.  Any pre-existing urological conditions had been treated and resolved
    or were under control.

7.  Patient must be a good surgical candidate,

8.  Patient must be 21 years of age or older.

**Patient Exclusion Criteria**

Any one of the following criteria excluded the patient from the study.

1.  Patient had previously received an artificial urinary sphincter
    prosthesis implant or other urogenital implant.

2.  Patient had a history of sensitivity to silicone.

3.  Patient did not speak English (the exclusion of non-English speaking
    patients was necessary because the quality of life survey
    instruments had not been validated in non-English speaking
    populations).

4.  Patient's reading level was judged to be inadequate for reading and
    understanding the patient labeling (reading must have been at least
    seventh grade level).

5.  Patient's health would have precluded completion of the follow-up,
    including terminal illnesses.

6.  Patient refused to, or was unable to, comply with the requirements
    of the protocol.

7.  Patient's urinary incontinence was less than 6 months in duration,
    post- TUR, TURP, or radical prostatectomy and/or primary etiology of
    incontinence was not one of the above three procedures.

8.  Patient presented with a neurogenic bladder condition that was not
    treatable or controllable by pharmacological or alternative methods.

9.  Patient had a history of connective tissue or autoimmune conditions.

10. Patient had uncontrolled diabetes as confirmed by glycosylated
    hemoglobin measurement.

11. Patient had post void residual urine ≥ 75 cc.

12. Patient had an active abscess or infection.

**Demographics/Etiology**

Eighty-seven (87) male patients who developed urinary incontinence
following prostate surgery were enrolled in the study. Except for 1
Black and 1 Asian, all other patients (85, i.e., 97.7%) were Caucasian.
Of these 87 patients, 76 (87.4%) were post- prostatectomy patients and
11 (12.4%) were post- TUR (transurethral resection) patients. Mean age
of the patients was 67.7 years.

**Medical History**

Fifty-eight patients had cardiovascular conditions, 40 had
musculoskeletal conditions, 8 had neurological conditions, 15 had
bladder dysfunction (e.g., fibrotic bladder, detrusor instability, low
bladder capacity), 3 had chronic urinary tract infection (UTI), 46 had
erectile dysfunction and 37 had strictures. All the patients were
required to complete a Connective Tissue Disease Screening Questionnaire
(CTD-SQ) prior to implantation. Eighty-five (85) of the 87 patients
enrolled in the study completed the CTD-SQ. None of the patients showed
positive results on rheumatology review of the responses to the
questionnaire.

**Pre-Implant Urological Procedures**

Of the 87 patients enrolled, 15 had pelvic radiation, 9 had pelvic
surgery, 8 had bladder neck surgery, 7 had TUR-Prostrate (not primary
surgery), 33 had none and 32 had other procedures. Some of the "other
procedures" were bladder neck contracture, bladder neck incision,
radiotherapy for prostrate cancer, dilatation, Direct Vision internal
Urethrotomy, suprapubic prostatectomy and suburethral sling.

**Pre-Implant Management of Incontinence**

The surgical implantation of AMS Sphincter 800™ Urinary Prosthesis was
not the first treatment or management option for the 87 enrolled
patients. Eighty-one patients reported using one or more methods. The
most commonly used management method was absorbent pads (80 patients).
Twenty-six patients used pharmacologic treatment, 31 patients had
periurethral collagen injections, 21 used Cunningham clamp, 15 used
condom catheter, 9 had biofeedback therapy, 4 had electrical
stimulation, 13 had other behavioral modification techniques and 3 had
urological surgery.

**Deactivation of AMS Sphincter 800™ Urinary Prosthesis**

After surgical implantation of AMS Sphincter 800™ Urinary Prosthesis in
the patient, the surgeon deactivates the device by pressing the
deactivation button in the pump to empty the fluid in the cuff and allow
healing of the urethral tissue for 4-6 weeks. In the deactivated state,
the cuff remains empty and the patient manages his incontinence with
other methods such as absorbent pads. At the follow-up visit after the
healing period, the physician activates the device. The activation is
achieved by squeezing the lower part of the pump implanted in the
scrotum. On activation, the cuff is refilled with the fluid to close the
urethra and maintain continence.

**Follow-up**

The first office visit was scheduled 4-6 weeks post-implantation for
activation of the device and incontinence assessment. If the assessment
did not occur at this Activation visit, a First Post-Activation
follow-up visit was scheduled before the 6-month visit. Patients were
followed at 6, 12, 18 and 24 months post-implant. Sixty-seven patients
had 6-month follow-up, 60 patients had 12-month follow-up, 55 had
18-month follow-up and 41 patients had 24-month follow-up.

**Patient Accountability**

Of the 87 patients enrolled, one patient withdrew before implantation
and one patient was not implanted as of the data cut-off date. Of the
remaining 85 patients implanted, one patient had the device removed
prior to activation due to infection and activation data was not
submitted for 4 patients prior to database closure, leaving 80 patients
with activation data.

Thirteen (13) of the 87 enrolled patients did not complete the study.
Three of the withdrawals were due to deaths and they were determined by
the investigators not to be related to the device. The reasons for
discontinuation are shown in Table 2 below.

Table 2. Reasons for Patient Discontinuation from the Prospective Study

  ----------------------- ----------------------- -----------------------
                          n=87                    \%

  Reason                                          

  Change in Medical       3                       3.4
  Condition\*                                     

  Patient Death           3                       3.4

  Device Explanted\*\*    4                       4.6

  Missed Visits           2                       2.3

  Withdrew Prior to       1                       1.1
  Implant                                         
  ----------------------- ----------------------- -----------------------

8 patients were withdrawn by investigators and 5 patients withdrew
themselves.

\*Withdrawal due to prostate cancer (2) and progressive dementia (1).

\*\* Device Explanted, not reimplanted, Erosion (1); Erosion due to
Foley Catheter placement for unrelated procedure (1); Infection and Pain
related to urethrocutaneous fistula (1); In fection following Y-V plasty
for bladder neck contracture unrelated to device (1).

**Endpoints**

The primary effectiveness end point was to evaluate the effect of AMS
Sphincter 800™ Urinary Prosthesis on quality of life using an
Incontinence Impact Questionnaire (IIQ)(Schumaker et al, Quality of Life
Research, 3:291-306, 1994)). The IIQ is a validated instrument designed
to assess the impact of incontinence on several subscales, including
physical, social and emotional scales. The secondary effectiveness
endpoints used Health Status Questionnaire (HSQ)(Health Outcomes
Institute, HSQ 2.0, 1993 and RAND 36-item Health Survey, 1.0, 1986), and
Rosenberg Self-esteem Scale (Rosenberg M. Society and the Adolescent
Self Image, Princeton University Press, 1965) for measuring the effect
of the device on general quality of life. The HSQ is a slightly modified
version of the MOS-20 that was validated as part of Rand Corporation's
Medical Outcomes study. The HSQ added 3 questions to MOS-20 about
patients's feeling depressed during 2 years after the device
implantation. In addition, the physician and patient also evaluated the
improvement in patient's incontinence after the sphincter implantation.
The primary safety objective or endpoint of the study was to verify by
Bayesian analysis that the AMS Sphincter 800™ Urinary Prosthesis has 75%
(within delta of 10%) revision free rate found in the PIF Study.

**Effectiveness**

**Primary Effectiveness Endpoint: Incontinence Impact Questionnaire**

The Incontinence Impact Questionnaire used for determining primary
effectiveness is a 30-item, validated, self-administered questionnaire
designed to assess the impact of urinary incontinence on several aspects
of patient's life, including physical, emotional, social and sexual.
Incontinence Impact was measured pre- and post- implant at 6, 12, 18 and
24 months. Thirty-nine (39) patients answered the IIQ at 24 months
post-implantation. The higher score indicates greater impact of urinary
incontinence on the quality of life. At 2-year follow-up, the mean score
was 51, compared to pre-implant score of 143. The mean pre-implant score
was significantly higher (p\>0.001) than the mean score at all follow-up
visits, indicating statistically significant improvement in the
patient's quality of life.

**Secondary Effectiveness Endpoints**

Patient responses to Health Status Questionnaire and Rosenberg
Self-esteem Questionnaire were also evaluated at all four follow-up
visits. Thirty-eight (38) patients responded to these questionnaires at
24 months post- implantation. The HSQ was used to assess non-illness
aspects such as physical functioning, social functioning,
energy/fatigue, pain, health perception and emotional problems. No
significant improvement was noted in the health status of the patients
at 24-month follow-up. The responses to Rosenberg Self-esteem
Questionnaire were used to assess changes in patient self-esteem. In
this self-esteem evaluation, the scores ranged from 0 to 6, with a score
of 6 indicating high self-esteem. At 2-year follow-up, the mean
self-esteem score was 4.1 compared to the mean pre-implant score of 3.5,
indicating an increase in self-esteem after the AMS Sphincter 800™
Urinary Prosthesis implantation. The increase in self-esteem scores was
statistically significant. The positive impact of the device on
patients' lives observed in this clinical study is consistent with the
results reported in the literature (Haab *et al*, Journal of Urology,
158:435-439 (1997); Litwiller *et al,* Journal of Urology, 156:1975-80
(1996); Fleshner and Herschorn, Journal of Urology, 155: 1260 (1996)).

Physician and patient assessments of incontinence status after AMS
Sphincter 800™ Urinary Prosthesis implantation are shown in the Table 3
below.

Table 3. Patients' Incontinence Status after AMS Sphincter 800™ Urinary
Prosthesis Implantation.

  -------------- -------------- -------------- -------------- --------------
  Evaluator      Follow-up      \# Patients    Dry            Up to 3
                                                              pads/day

  Physician      1-year         43             63.6%          34.1%

  Physician      2-year         30             73.3%          23.3%

  Patient        1-year         60             61.7%          36.7%

  Patient        2-year         41             65.9%          31.7%

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

These results show that there was no significant difference between
physician's and the patients' assessment of the improvement in patient's
incontinence.

**Sexual Function**

A question in regard to sexual function was also included in the IIQ.
The question asked patients how the device affected their sexual
relationship: not at all, slightly, moderately or severely. Forty-six of
the 87 enrolled patients reported erectile dysfunction pre-implant,
leaving 41 patients with erectile function. According to the information
provided in the PMA, although only 16 of these 41 patients had 2-year
follow-up, none of the patients reported erectile dysfunction
attributable to the device at any of the follow-ups and there was also
no report of sexual dysfunction in the sponsor's database or in any of
the numerous publications on the device. In their publication, Litwiller
et al reported improvement in sexual function in 7 of the 50 patients
that they followed.

**Safety**

**Primary Safety Endpoint: 5-year Revision-Free Rate**

The primary safety endpoint of the study was to demonstrate that the
5-year revision-free rate (i.e., the device or its component does not
need replacement or removal) was not less than 65% (75% minus delta of
10%). Since the Prospective Study followed patients for only 2 years,
only the 2-year revision-free rate could be obtained directly. The
2-year revision-free rate was 68.35% and the 1-year revision-free rate
was 90.5%. An estimated 5-year revision-free rate of 74% with 95%
confidence interval is shown in Figure 2. The 5-year revision-rate was
calculated borrowing a large amount of data collected on 875 patients)
in the PIF Study and using Bayesian statistical methods.

> ![](media/image2.wmf)**FIGURE 2**

Of the 85 implanted patients, 14 patients (16.5%) required a total of 15
revision surgeries over a period of 2 years. Two revisions in 2 patients
were not considered device-related. One of these two patients had an
infected wound and the other patient had pain at the base of the penis
pre-implant and in the scrotum post-implant. Four of these 14 patients
underwent device removal and subsequently exited from the study. The
remaining 10 patients underwent device replacement or revision and
remained in the study. Details about the revisions in the Prospective
Study are presented with revisons in PIF and Prospective studies (Table
4).

**Device Related Adverse Events**

As pointed out earlier, a total of 43 adverse events in 26 patients were
reported to be device related. The various device- related adverse
events are shown in Table 4 below.

Table 4. Device Related Adverse Events in Prospective Study

Event Category Total Events No. of Patients

Compromised Device function 7 6

Pain/discomfort 6 5

Delayed Wound Healing 5 5

Migration 3 3

Recurrent Incontinence 3 3

Bladder Spasms 2 2

Difficult Activation 2 2

Tissue Erosion 2 2

Infection 2 2

Swelling 2 2

Fistula Formation 1 1

Hematoma 1 1

Hydrocele 1 1

Tissue Erosion/Infection 1 1

Patient Dissatisfaction 1 1

Positional Incontinence 1 1

Wound Infection 1 1

Urinary Retention 1 1

Difficult Deactivation 1 1

The number of patients exceed 26 since the same patient had more than
one type of adverse event. Only one unanticipated adverse event was
reported involving Reactive Hydrocele with pain, discomfort and
swelling. Thirteen of the 43 events reported above were resolved with no
intervention. The remaining events required medical and/or surgical
intervention, including revision surgeries.

**Non-Device Related Adverse Events**

A total of 129 events in 85 patients were reported that were not related
to the device. Sixty-three (63) events were categorized as urogenital in
nature. Twenty cardiovascular events occurred in 18 patients and 14
musculoskeletal events occurred in 11 patients. None of the
musculoskeletal events were considered related to the sphincter device
by the physician. AMS supported the physician's determination by noting
hat the published literature on silicone devices does not show any
causal relationship between silicone and any suspected autoimmune
diseases.

**[PIF Study]{.underline}**

As indicated earlier, the PIF Study is the largest (12713 male patients)
and is based on the information contained in the patient information
forms returned to AMS by implanting physicians after implantation of AMS
Sphincter 800™ Urinary Prosthesis and/or replacement of the device or
its component. The forms typically provide information on the medical
history of the patient, etiology of incontinence, date of original
implantation surgery, cuff location, replaced component, date of
revision surgery and reason for revision. The forms do not contain
information about the effectiveness of the device and they do not
provide information on adverse events associated with the device other
than the adverse event or reason for the revision surgery. Therefore,
the data collected under the PIF Study is essentially limited to
information regarding revisions and survival of the device.

**Demographics and Etiology**

The PIF Study patients were implanted with AMS Sphincter 800™ Urinary
Prosthesis during 1995-1999. The PIF database referenced in the PMA has
a total of 12713 males, 96 females and 262 children. Only the data
collected on males were used for the estimation of a revision-free rate
and evaluation of the reasons for revision for comparison with the
results of the Prospective Study. Although the PIF Study did not have
the same eligibility criteria as the Prospective Study, they were close
in regard to several criteria. For instance, average age of the PIF
patients was 68.5 years versus 67.7 years of the Prospective Study. The
etiology of the PIF Study male patients with 77.4% post-prostatectomy
and 6.65% post-TUR closely matched the etiologies of the Prospective
Study population. In regard to prior treatments, only 8.1% PIF patients
had urethral bulking injections compared to 36.8% in the Prospective
Study. Eighty five percent (85%) of PIF males had the cuff placed at
bulbous urethra, compared to 100% in the Prospective Study. These
characteristics show a close similarity of patients in both studies for
comparison of revision-free rates and to qualify the ue of data from the
PIF Study to estimate the 5-year revision-free rate for the Prospective
Study patients, using Bayesian statistical methods.

**Revision Rates and Reasons for Revision**

The data presented in the PMA shows that the overall 5-year
revision-free (device survival) rate for the AMS Sphincter 800™ Urinary
Prosthesis was 75%. A comparison of the reasons reported for revision
surgeries in other studies is presented in table 4

**[Retrospective Study]{.underline}**

The Retrospective Study is intended to provide both safety and
effectiveness information over long-term follow up as long as 9 years.
In this study, 390 male patients were implanted with the AMS Sphincter
800™ Urinary Prosthesis to treat urinary incontinence following prostate
or sphincter surgery. Radical prostatectomy was the most common etiology
(65.6%) and TUR-prostrate was the next common etiology (28.5%). The
device was implanted in the patients between 1987-1990 at 12 centers in
the U.S. Post-implant data was obtained for 356 patients.

The limitation of this study is follow-up times were not specified and
physician follow-up occurred on only 19.5% (76/390) of the implanted
patients. It is unclear how many patients were followed at each follow
up interval. There is also no data on when revision surgeries were done.
Therefore, it was not possible to calculate a revision-free rate using
Kaplan-Meir method to compare with rates estimated in the PIF Study and
Prospective study. Disregarding device revisions, the probability of
device use for 9 years in 323 patients was estimated to be 83.9%.

**Revision Rates and other Information**

This study collected general information on the number of revisions,
reasons for revision, and patient satisfaction with the device. The
revision rates in this study are presented in Table 4 along with similar
information for the Prospective and PIF Studies.

**Effectiveness: Degree of Continence**

The Retrospective Study reports Physician and Patient Assessments on the
degree of continence achieved without specifying when the assessment was
made. If the time of assessment is not considered, continence rates are
reported as follows. Physician follow-up on 79 patients notes 8 (10.1%)
were dry, 17 (21.5%) required no protection and 40 (50.6%) required up
to 3 pads/day. Telephone interview on 142 patients reports 48 (33.8%)
were dry, 62 (43.7%) required no additional protection and 12 (8.5%)
required up to 3 pads a day. If the criterion of up to 3 pads/day is
accepted as a reasonable degree of continence, this study data of 82-84%
are in good agreement with the Prospective Study results. However, it is
important to note that physician follow-up noted only 10% of the
followed patients as completely dry.

**Comparison of Revision Rates for Prospective, PIF and Retrospective
Studies**

Table 5 below provides stratified data by each reported reason for
revision in Prospective, PIF and Retrospective Studies. Under the PIF
Study and Retrospective Study, more than one reason may have been cited
for a single revision. Therefore, in order to stratify this revision
data by reason, all occurrences were included and presented as
"%reason". The total number of reasons therefore exceeds the total
number of revisions reported for these two studies.

# 

# 

#  Table 5: Reasons for Revision in 3 Different Studies 

+------------------------+---------------+--------------+-------------+
| ## Revision Reason ^a^ | **Prospective | **PIF        | **Retr      |
|                        | Study         | Study**      | ospective** |
|                        | (n=85)**      |              |             |
|                        |               | *            | **Study     |
|                        |               | *(n=12713)** | (n=356)**   |
+------------------------+---------------+--------------+-------------+
| ##                     | **% revisions | **% reason   | **% reason  |
|                        | (#            | (# reasons)  | (#          |
|                        | revisions)**  | ^b^**        | reasons)**  |
+------------------------+---------------+--------------+-------------+
| ## Infection           | > 2.4% (2)    | > 2.3% (297) | > 8.1% (29) |
+------------------------+---------------+--------------+-------------+
| ## Infection/erosion   | > 1.2% (1)    | > \-\-\-\--  | > \-\-\-\-- |
+------------------------+---------------+--------------+-------------+
| ## Erosion             | > 2.4% (2)    | > 3.6% (451) | > 22.5%     |
|                        |               |              | > (80)      |
+------------------------+---------------+--------------+-------------+
| Recurring Incontinence | > 2.4% (2)    | > 5.7% (724) | > 42.4%     |
|                        |               |              | > (151)     |
+------------------------+---------------+--------------+-------------+
| ## Fluid Loss          | > \-\-\-\--   | > 2.3% (298) | > 9.3% (33) |
+------------------------+---------------+--------------+-------------+
| Fluid Transfer         | > \-\-\-\--   | > 0.3% (38)  | > \-\-\-\-- |
| impaired               |               |              |             |
+------------------------+---------------+--------------+-------------+
| ## Pressure too low    | > \-\-\-\--   | > 1.1% (140) | > \-\-\-\-- |
+------------------------+---------------+--------------+-------------+
| Mechanical Malfunction | > 3.5% (3)    | > 0.7% (89)  | > 13.8%     |
|                        |               |              | > (49)      |
+------------------------+---------------+--------------+-------------+
| Migration/Malposition  | > 3.5% (3)    | > 0.4% (46)  | > 4.8% (17) |
+------------------------+---------------+--------------+-------------+
| Iatrogenic             | > \-\-\-\--   | > 0.4% (51)  | > 0.6% (2)  |
| Complications          |               |              |             |
+------------------------+---------------+--------------+-------------+
| Reimplantation/        | > \-\-\-\--   | > \-\-\-\--  | > 3.1% (11) |
| Replacement            |               |              |             |
+------------------------+---------------+--------------+-------------+
| ## Pain                | > 1.2% (1)    | > 0.2% (22)  | > 1.4% (5)  |
+------------------------+---------------+--------------+-------------+
| Patient                | > 1.2% (1)    | > 0.2% (27)  | > 1.7% (6)  |
| Dissatisfaction        |               |              |             |
+------------------------+---------------+--------------+-------------+
| ## Other ^c^           | > **\-\-\--** | > 2.4% (305) | > \-\-\--   |
+------------------------+---------------+--------------+-------------+
| ## Not indicated       | > **\-\-\--** | > 1.9% (242) | > \-\-\--   |
+------------------------+---------------+--------------+-------------+
| ##                     |               |              |             |
+------------------------+---------------+--------------+-------------+

> ^a^ Note that some adverse events in the table such as fluid loss,
> pressure too low, fluid transfer impaired and malposition could fall
> into the category of mechanical malfunction or iatrogenic error. Since
> information is not available to place them in either category, they
> are listed separately.
>
> ^b^ Numbers of reasons can vary for the same percentage due to
> rounding.
>
> ^C^ Other includes: double cuff, pressure too high, unable to
> activate, unable to deactivate, atrophy, difficult to operate, urinary
> retention, air in the system, hematoma.

Table 6 presents the percentage of patients revised during a specified
follow up period, the average number of revisions performed on patients
requiring a revision and the total number of revisions performed per 100
patients in the Prospective, PIF and Retrospective Studies. This table
shows that the percentage of patients who underwent revision surgery and
the number of revisions per 100 patients are almost the same in both
Prospective and PIF studies, but much higher in the Retrospective Study.
Longer follow up (9 years) may be the reason for higher revision rates
in the Retrospective Study.

Table 6. Revision Rates in 3 Different Studies

  ----------------- ----------------- ----------------- -----------------
  Type of Study     Prospective       PIF Study, 12713  Retrospective
                    Study, 85         Patients over 5   Study 356
                    Patients. over 2  years             Patients over 9
                    years                               years

  \% Pts Revised    16.5% (14/85)     15.8%             46.1% (164/356)
                                      (2014/12713)      

  Average \# of     1.07 (15/14)      1.05 (2116/2014)  1.93 (317/164)
  Revisions per                                         
  Pts. Revised                                          

  \# of Revisions   18 (15/85)        17 (2116/12713)   89 (317/356)
  per 100 Pts.                                          
  ----------------- ----------------- ----------------- -----------------

**[Published Reports of Clinical Experience]{.underline}**

Published reports of clinical experience using AMS artificial urinary
sphincters dates back to 1973 when Drs. Scott and Bradley reported five
successful cases using AMS' first fully implantable hydraulic urinary
prosthesis. For the period 1985-2000, 67 articles appeared containing
clinical experience on 4,127 AMS artificial urinary sphincter
recipients. Analysis was not performed on this group of patients. The
literature for this period includes long-term results for multiple
patient series equal to or greater than 100 patients. A review of the
articles showed successful outcomes (acceptable continence) ranging from
74%-100% and complications were either manageable through medical
intervention or resolved without intervention. Erosion and infection
were manageable and within acceptable rates for prosthetic surgery.
Design modifications have improved mechanical reliability. Several
studies measure patient satisfaction using standardized instruments. The
results generally found high rates of satisfaction among AMS 800
patients. Patient satisfaction did not depend on achieving total
continence and was not affected by revisions.

A selection of published reports on AMS Sphincter 800™ Urinary
Prosthesis is summarized below. Most of these reports or studies are
selected on the basis that they discuss the outcome in a group of men
greater than 100. However, a few reports on less than 100 men are also
selected to illustrate a specific effect of the device such as the
effect on quality of life or the effect of a design change (e.g., double
cuff).

Hajivassiliou (European Urology, 35, 36-44(1999)) performed a
meta-analysis using several reports published during 1985-1993 on 2,606
patients implanted with an AMS Sphincter 800™ Urinary Prosthesis to
treat urinary incontinence due to ISD of various etiologies. Only 60% of
these patients were post-prostatectomy patients in comparison with 87%
in the Prospective Study and 77% in the PIF Study. The calculated global
success rates and complication rates are shown in the Table 6 presented
below.

TABLE 7 Calculated global success rates and complications of the AMS
800. Meta-analysis from 2,606 patients

  ------------------------------------------------- ---------------------
  **Category**                                      **Global rate (%)**

                                                    

  Improved continence                               88.1

  Fully continent                                   73.0

  Revisions (total)                                 31.9

  Urethral erosion                                  11.7

  Infection                                         4.5

  Mechanical complications                          13.8

                                                    

  *Data from Hajivassiliou 1999*                    
  ------------------------------------------------- ---------------------

The table shows that 73% of the implanted patients became continent and
a total of 32% implanted patients required at least one revision. Fifty
percent of the revisions were performed within 8 months and 90% within 3
years of implantation. Mechanical failure accounted for 14% of the
complications.

Hajivassiliou also conducted a retrospective review of patient reports
on complications following the implantation of AMS Sphincter 800™
Urinary Prosthesis during a period between February 1986 and June 1994
(8.4 years) in FDA database and found 4130 complications in 3508
patients. Since the device has been reported to be implanted in an
estimated 20,000 patients all over the world by AMS, the global
complications rate was estimated to be 21%. Mechanical malfunctions and
complications accounted for 22.1% of the total complications. Failure of
the pump accounted for 35.6%, cuff related complications accounted for
43.8% and balloon related complications accounted for 12.6% of the total
mechanical complications. In addition, 12.9% of the reported
complications in the database were due to infections. Any comparison of
these rates with the rates of complications observed in the Prospective
Study, PIF Study or Retrospective Study should note that only 60% of the
patients in Hajivassiliou's analysis were men with prostatectomy
etiology and the rest were children and women.

Even though the global rates were adjusted to account for different
numbers of patients in each study, the author notes that many of the
small cohorts may have a significant bias depending on whether follow-up
documentation was done under "good clinical practice" conditions.

Incontinence improved in nearly nine out of ten patients. About seven
out of ten patients were dry. The global rate of mechanical malfunctions
was 13.8%. Cuff leaks due to fold wear were the most frequent cause of
mechanical failure. A surface treated cuff was introduced in 1983 and
the incidence of leakage decreased from 12.5% to 1.3%. Over one in ten
patients experienced urethral erosion while the infection rate was less
than 5%.

The calculated global urethral erosion rate was 11.7%. The balloon
pressure in the cases with urethral erosion was not reported
consistently in the literature. In one study (Furlow 1981), all patients
with urethral erosion had been implanted with balloons \>80 cm H~2~O.
None of the patients with balloons \<70 cm H~2~O had urethral or bladder
neck erosion. Self-catheterization has been reported as an adjunct to
AMS Sphincter 800 Urinary prosthesis implantation. The low rate of
post-catheterization erosion reports (5) in this review indicates that
careful self-catheterization may be safe. Hajivassiliou concludes that
the AMS Sphincter 800 Urinary Prosthesis implanted in carefully
selected patients has a high success rate and a low complication rate.
Patients with adverse implantation features (e.g. pelvic irradiation)
should not be deprived of the treatment option if meticulous technique
(including primary deactivation) is adhered to and patient selection is
appropriate.

Elliott and Barrett (Journal of Urology, *159,* 1206-1208 (1998))
reported on 323 patients who received AMS Sphincter 800™ Urinary
Prosthesis from one surgeon between 1983 and 1994 for correction of
severe urinary incontinence. The patients were followed for at least 18
months. The mean follow up was 68.8 months. Of the 323 patients, 313
were men and 10 were women. In their publication, they separated
mechanical and nonmechanical failures. They also analyzed reoperation
rates before (during 1983-87) and after (1988 to 1994) the introduction
of the narrowback cuff. Their results show that the use of narrow back
cuff significantly decreased reoperation rates and failure rates as
follows: 42% (58 of 138) patients in the pre-narrow back cuff group
required one revision surgery compared to 17% (31 of 184) patients in
the narrow back cuff group. Using Kaplan-Meir statistical analysis, the
5-year product survival (revision-free rate) was calculated to be 75%
for the narrow back cuff device. Mechanical failure occurred in 21% (29
cases) with the pre-narrow back cuff and 8% (14 patients) with the
narrow back cuff. Mechanical failures consisted of cuff leak, pump
malfunction, balloon leak, tubing leak, tube kinking, pump leak and
connector separation. Nonmechanical failures developed in 17% (24 cases)
with the pre-narrow back cuff versus 9% (17 cases) with the narrow back
cuff. Nonmechanical failures involved cuff erosion, infection, decrease
in cuff size or increase in balloon reservoir pressure, pump
malposition, tubing erosion and tandem cuff placement. Ultimately 437
operations were required in 323 patients, of whom 234 (72%) required no
further surgical intervention at a mean follow up of 68.8 months.

Leo and Barrett (Journal of Urology, *150,* 1412-1414, (1993) also
report on the success of narrowback cuff design. They analyzed the
results on 144 patients (136 male and 8 female). Mean follow up was 28
months. The cuff was placed around the bulbous urethra in 107 patients
and around the bladder neck in 37 patients (29 male and 8 female). One
hundred and five(105) patients had radical or subtotal prostatectomy.
They state that "two of the most clinically significant complications
are recurrent incontinence caused by underlying urethral tissue atrophy
and erosion of the cuff through the smooth muscle of the urethra". The
narrow back cuff design was introduced in 1987 to address these
complications. Of the 144 patients, 125 (87%) required no revision, and
therefore, the reoperation rate was 13%. The authors conclude that this
design change and the use of the 4.5 cm cuff with the 61-70 cm. pressure
balloon decreased the incidence of cuff erosion and the need for
reoperation for inadequate cuff pressure. On the basis of external pad
use, the authors report satisfactory continence (2 less pads a day) by
88% of their patients.

Martins and Boyd (British Journal of Urology, *75,* 354-358 (1995))
reported on 145 male patients who had AMS Sphincter 800™ Urinary
Prosthesis implanted between January 1987 and November 1993. The mean
follow up was 343 months (range 1-83). The authors report that
infection/erosion occurred in 13 patients (9%). All 13 patients had
undergone radical retropubic prostatectomy, radical cystectomy and
abdomino-perineal resection. Seven patients had also received radiation
therapy. Cuff placement was bulbar in all 13 patients. These authors
conclude that, "despite all the precautions taken, there remains a group
of patients who are still at a higher risk of infection-erosion due to
adverse circumstances that distort the anatomy of the perineal area,
impair the host defense mechanisms, and ultimately enable the
establishment of the infection-erosion complex. Radiotherapy is known to
increase the likelihood of nonmechanical complication, specifically
infection-erosion".

Light and Reynolds (Journal of Urology, *147*, 609-611 (1992)) also
reported on the impact of the cuff design changes in reducing
complications. Mean follow-up for the narrow back cuff was 27 months. A
total of 146 cuffs were implanted in 126 (88 male and 38 female)
patients. The incidence of cuff leaks was 1.3%, while the overall
revision rate for clinically significant pressure atrophy was 9%.

Montague (Journal of Urology, 1*47,*380-382 (1992)) reported on the
treatment of 166 patients (156 male and 10 female) with AMS Sphincter
800™ Urinary Prosthesis . One hundred and nineteen (119) male patients
had either total prostatectomy or subtotal prostatectomy. Mean follow up
was 41.6 months (range 6 to 94 months). A total of 40 reoperations (27
revisions and 13 device removals) were performed in 32 of the 166
patients (19.3%). There were 13 mechanical device failures (7.8%), 11
cuff erosions (6.6%) and 2 prosthesis infections (1.2%). Eighty-eight
(48.8%) patients used no pads, 44 (26.5%) used one pad a day for "near
total continence rate" of 75.3%. Eighteen (10.8%) more patients used 3
or less than 3 pads/day.

Kowalczyk et al. (Journal of Urology, *156*, 1300-1301 (1996)) reported
cuff erosion rate of 10.5% in men who received AMS Sphincter 800™
Urinary Prosthesis for their stress incontinence following
prostatectomy. Their study involved 95 men of whom 90 received a double
cuff (two cuffs). They conclude that addition of a second cuff to the
artificial urinary sphincter remains a safe alternative for patients
with severe urinary stress incontinence as pointed out by Brito et al.
(Journal of Urology, *149,* 283- (1993)) who implanted 15 patients with
double cuff. Kabalin (Journal of Urology, *156,* 1302-1304 (1996)) notes
that stress urinary incontinence may persist in approximately 15% of men
following implantation of a standard artificial urinary sphincter and
recommends implantation of a second urethral cuff to provide
satisfactory urinary continence in men with an artificial urinary
sphincter and persistent incontinence. In Kowalczyk's study, the rate of
socially acceptable dryness, as defined by Montague, remained greater
than 95% in their patients with the double cuff sphincter.

Mottet et al. (Urology International, *60,Supplement 2, 25-29* (1998))
reported on 103 men who were implanted with AMS Sphincter 800™ Urinary
Prosthesis for urinary incontinence following radical prostatectomy. The
follow up ranged between 1 and 3 years. In these patients, 12% revisions
were due to infection/erosion and 10% revisions were due to mechanical
failures. Sixty one percent (59 patients) were dry and 28% (27 patients)
had leakage of a few drops.

Heitz (Journal of Urology, Supplement 4, Abstract #1029 (1997) reported
on 321 male patients who suffered from iatrogenic incontinence due to
radical prostatectomy. Thirty one (9.6%) patients had revisions due to
mechanical (cuff leakage) problems and 64 (19.9%) patients had revisions
for non-mechanical problems (45 for tissue atrophy, 11 for infection and
cuff erosion and 8 had device removed permanently). The overall revision
rate for mechanical and non-mechanical causes was 29.5%. Regarding
benefits, 277 (86%) patients were completely dry or used 1 pad/day.
Nineteen (6%) patients used 2-3 pads/day and 17 (5%) patients were
treatment failures. The authors conclude that AMS Sphincter 800™ Urinary
Prosthesis has proven to be a safe and reliable treatment option for
post-prostatectomy incontinence.

Haab et al. (Journal of Urology, *158,* 435-439 (1997)) reviewed the
medical records of 68 male patients treated at their institution between
March 1980 and March 1992. Sixty-four of the 68 patients had
prostatectomy etiology. Mean follow-up was 7.2 years. In this group, 11
patients had revision surgery for mechanical complications and 10
patients had revisions for non-mechanical complications (urethral
atrophy 6, urethral erosion 2, tubing erosion 1, permanent scrotal
pain 1) for a total of 21 (31%) patients with revisions. Thirty-one
(61%) patients were alive with functioning sphincter and satisfied after
10 years. Fifty-four (80%) patients were socially continent using 0-1
pad/day. Of the 52 patients who were available for long-term survey of
quality of life, 88% percent of the patients would undergo treatment
again and 85% would recommend treatment to a friend. The authors
conclude that their long-term study documents the positive impact of the
artificial urinary sphincter on patient quality of life with few
mechanical failures.

Herschorn et al. (Journal of Urology, *155), Abstract \# 583 (May* 1996)
reported on the treatment of 123 males and 11 females. Sixty-eight
patients were post- radical prostatectomy patients and 32 were
post-TURP. Not all but most patients received AMS Sphincter 800™ Urinary
Prosthesis with new modifications, as they became available. Mean
follow-up was 37.6 months. Forty-four (32.5%) patients required
reoperations, 16 had more than one reoperation and 9 had the device
removed permanently. In 15 (12.2%) patients, the revisions were due to
device failure (mechanical problems). Non-mechanical problems accounted
for revisions in 29 (23.5%) patients. Fifteen patients (12.2%) had
reoperation for persistent incontinence and 14 (11.4%) had revisions due
to infection and/or erosion. The radical prostatectomy group underwent
fewer revisions (13/69=19%). Median survival of the device was 85.2
months.

Litwiller et al. (Journal of Urology, *156,* 19775-1980 (1996)) reported
on 65 male patients with AMS Sphincter 800™ Urinary Prosthesis for their
post-prostatectomy incontinence over a period of 9 years. In this group
of 65 patients, the revisions totaled 18%; 9% due to atrophy 6% due to
infection and 3.1% due to erosion. For documenting patient satisfaction
with the treatment, the authors were able to survey only 50 patients
using telephone interview or written questionnaire. Mean follow-up was
23.4 months. The long-term complete continence rate was only 20%. Of the
patients with wetness, 55% had leakage of a few drops daily and 22% had
leakage of less than a teaspoon. These results indicate that 97% of the
surveyed patients had acceptable continence. In the survey, a total of
90% of the patients reported satisfaction with the AMS Sphincter 800™
Urinary Prosthesis and 96% stated that they would recommend the device
to a friend. Seven (14%) patients reported improved sexual activity.

Fleshner and Herschorn (Journal of Urology, *155,* 1260-1263 (1996))
interviewed and also collected responses to a standard questionnaire
regarding their activities of daily living and quality of life from 30
men who received AMS 800 sphincter following radical prostatectomy. They
conclude that the artificial urinary sphincter is an effective form of
therapy for post-radical prostatecomy incontinence but irritative
voiding symptoms occur, which tend to limit activities of daily living.
Since the authors state that these patients were implanted with the
sphincter device during the last 14 years, not all patients would have
received AMS Sphincter 800™ Urinary Prosthesis. Therefore, the
irritative voiding symptoms may not be attributable to the modern AMS
Sphincter 800™ Urinary Prosthesis model with narrow back cuff design
introduced in 1987.

**[Risks versus Benefits]{.underline}**

There are some risks associated with AMS Sphincter 800™ Urinary
Prosthesis implant. In addition to the risks involved with the surgical
procedure to implant the device, several risks associated with the
device have been documented in numerous publications over the years and
in the 3 studies conducted by AMS. The rates of some risks, especially
tissue erosion from cuff pressure have decreased after the introduction
of the narrow back cuff design in 1987 and the use of a double cuff in
some patients. Still the PIF Study, the Prospective Study and the
Retrospective Study indicate the risks are not negligible as discussed
earlier. The rates for various risks were: Infection 2.3- 6.7%; Erosion
2.4-16.2%, Fluid Loss 2.3-7.0%, Mechanical malfunction 0.66-10.6%,
Migration 0.36-4.7%, Recurring incontinence 1.2-27.2%. Often these risks
require operation.

Although the risks are not insignificant, the benefits of AMS Sphincter
800™ Urinary Prosthesis outweigh these risks for the intended use of
treating urinary incontinence due to intrinsic sphincter deficiency
following prostate surgery. The most important factors to be considered
are: 1) the device is not the first choice but the last choice for the
patients who have severe incontinence resulting from prostate surgery
and 2) there is no other artificial sphincter device available in the
market for these patients. The literature and the studies referenced in
this PMA indicate that 65-70% of the patients achieve dryness, 90% of
the patients achieve reasonable improvement in their incontinence (up to
3 pads/day) and 90-95% of the patients expressed satisfaction with the
device because it improved the quality of their lives.

**XI. CONCLUSIONS DRAWN FROM STUDIES**

Preclinical studies assessed the device design, mechanical properties,
reliability, and materials biocompatibility. Results from this testing
provide assurance that the device design is appropriate for the intended
use. The published literature as summarized above provides additional
evidence to support the decision that the device is reasonably safe and
effective for its intended use.

Results from the Prospective Study indicate that quality of life
improved for patients treated with the AMS Sphincter 800 Urinary
Prosthesis, as measured by the Incontinence Impact Score and Rosenberg
Self-Esteem Scale. Continence status also improved for most patients.
After two years, physician assessment of continence was 73.3% of
patients were completely or substantially dry and 23.3% only required
some additional protection. Patients' assessment of continence was
consistent with the physicians'. The estimated 5-year revision-free rate
of 74%, based on hierarchical Bayesian model, is in close agreement with
the data available in the PIF Study and published literature. The
Prospective Study provided no additional information that affects the
known safety and effectiveness profile of the device for this specific
patient population.

**XII. PANEL RECOMMENDATIONS**

The PMA was not referred to the Gastroenterology and Urology Devices
Advisory Panel for review and recommendations since the device has been
marketed for 17 years and extensive literature exists on the performance
of the device.

**XIII. CDRH DECISION**

Based on the information provided in the PMA, CDRH has determined that
the AMS Sphincter 800™ Urinary Prosthesis is reasonably safe and
effective for the indication of treatment of urinary incontinence due to
reduced outflow resistance (intrinsic sphincter deficiency) following
prostate surgery.

The device manufacturing facility of American Medical Systems and
sterilization sites were inspected and found to be in compliance with
the Quality System Regulation (21CFR 820).

**XIV. APPROVAL SPECIFICATIONS**

: [Labeling:]{.underline} See the Physician and Patient Brochures that
are described below.

-   AMS Sphincter 800™ Urinary Prosthesis, Package Insert

-   AMS Sphincter 800™ Urinary Prosthesis, Operating Room Manual

-   Patient Information and Instructions for the AMS Sphincter 800™
    Urinary Prosthesis

[Hazards to Health from Use of the Device]{.underline}:

See Indications, Contraindications, Warnings, Precautions and Adverse
Events in the labeling.