**SUMMARY OF SAFETY AND EFFECTIVENESS DATA**

I.  **GENERAL INFORMATION**

**Device Generic Name:** Device, Fecal Incontinence,

> Implanted

**Device Trade Name:** Acticon Neosphincter

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

10700 Bren Road West

Minnetonka, MN 55343

**PMA Number:** P010020

**Date of Panel Recommendation:** August 17, 2001

**Date of Notice of Approval to Applicant:** December 18, 2001

II. **INDICATIONS FOR USE**

# The Acticon Neosphincter is an implantable device used to treat severe fecal incontinence in males and females eighteen years and older who have failed, or are not candidates for, less invasive forms of restorative therapy. 

III. **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 fecal incontinence
complicated by an irreversibly obstructed proximal segment of bowel.

This device is contraindicated in patients with an active infection.

## WARNINGS AND PRECAUTIONS

**Warnings**

1.  Patients with diabetes, spinal cord injuries, musculoskeletal
    abnormalities, pre-existing stomas, or open sores in the region of
    the surgery have an increased risk of infection associated with a
    prosthesis. Patients who are immunocompromised or immunosuppressed
    may also be at a higher risk for infection associated with a
    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 explantation 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 misplacement. The cuff may erode around the anal canal or
    through the perianal skin. The control pump may erode through the
    scrotal or labial skin. The pressure-regulating balloon can erode
    into the bladder. Failure to evaluate and promptly treat the erosion
    may result in a substantial worsening of the condition leading to
    infection and/or loss of tissue.

3.  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.

4.  Surgical, physical, psychological, or mechanical complications, if
    they occur, 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.

> **Precautions**

### Patient Related Precautions

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 an Acticon Neosphincter. Although the
    prosthesis is designed to restore bowel 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 pain including severity and
    duration.

4.  Tissue fibrosis or previous surgery in the area of the implant may
    preclude implantation of an occlusive cuff at the anal canal.

5.  Acute bowel disorders, e.g. diarrhea or constipation, can interfere
    with proper functioning of the device and may require the use of
    external pads or manipulations to assist defecation.

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

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

8.  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.

9.  If radiopaque solution is used instead of sterile isotonic saline to
    fill the device, ensure the patient is not allergic to the
    radiopaque solution.

10. Receptive anal intercourse may damage the occlusive cuff and is not
    recommended for patients implanted with this prosthesis.

11. Vaginal delivery of children may interfere with future proper
    functioning of the occlusive cuff. Patients should be made aware of
    the need to discuss the presence of the Acticon device with their
    doctors should they become pregnant. A cesarean delivery may be
    recommended in order to avoid damage to the device.

12. No safety or effectiveness data exists for patients with a history
    of inflammatory bowel disease or pelvic radiation. The potential for
    increased risk of erosion in these patients is unknown.

#### Surgery Related Precautions

1.  Improper cuff sizing, improper balloon selection, or other causes
    such as surgical trauma, poor tissue viability, and concomitant
    medical procedures, 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
    lengths are incorrect. Migration can result in pain, complications,
    device malfunction and surgical revision.

3.  Unsuccessful outcomes may result from improper surgical 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 Precautions

1.  This device is subject to wear and eventual failure over time. It is
    not possible to predict how long the implanted prosthesis will
    function in a particular patient. The device should not be
    considered a lifetime implant.

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

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a)  In the event of large pressures within the bowel, automatic pressure
    relief that normally occurs with the device would be prevented.
    Cycling the device can relieve the fecal 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)  Release of the deactivation valve may require greater pressure than
    that used to cycle the device.

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3.  Use caution when passing any instrument through the anal canal. For
    certain procedures, e.g., anal ultrasound or colonoscopy, first
    deflate the cuff then deactivate the device prior to passing any
    instrument through the anal canal.

4.  System pressure changes may occur over time. This may result in
    changes in continence status. To increase system pressure, fluid may
    be added to the device through the septum port.

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IV. **ADVERSE EVENTS OF THE DEVICE ON HEALTH**

Discussion of adverse events is based on 115 patients implanted with the
Acticon Neosphincter in a multi-center, prospective study which
evaluated the safety and effectiveness of the device in patients with
severe fecal incontinence. A total of 456 adverse events were reported
during the clinical trial, 395 (86.6%) of which were considered to be
device-related or potentially device-related. One hundred and two (102)
of the 115 patients enrolled (88.7%) experienced at least one
device-related adverse event. Of these 395 device-related events, 358
(91%) were resolved by the conclusion of the clinical trial. With
respect to severity:

191 (48%) of the events were rated mild;

127 (32%) moderate;

55(14%) severe; and

22 (6%) were not rated.

With respect to the general modalities of treatment required to address
the adverse events:

17% required no intevention;

57% required medication or a non-invasive intervention; and

36% required surgical intervention.

Some of these adverse events may have required both a surgical and a
non-surgical intervention to resolve.

Among the 142 surgical interventions were 81 device revision procedures
during which part or all of the originally implanted prosthesis was
(were) repositioned, replaced, or removed. Fifty-six patients (56)
required at least one device revision as a result of adverse events.
Thirty-four (34) patients required total device explantation prior to
the conclusion of the study.

A summary of the adverse events recorded during the study along with
their frequency and method(s) of intervention are depicted in Table 1.
Of note, patients may have had more than one type of event or more than
one event of the same type. In addition, there may have been more than
one type of intervention for each event and patients may have had
multiple events treated with the same intervention.

Table 1: Adverse Events and Methods of Intervention for Acticon
Neosphincter Study

+---------------------+-------+------+--------+---------+------+-----+
| **Adverse Event**   | **N   | **Nu | **M    |         |      |     |
| **Type**            | umber | mber | ethods |         |      |     |
|                     | and   | of** | of     |         |      |     |
|                     | (%)** |      | In     |         |      |     |
|                     |       | **   | terven |         |      |     |
|                     | **of  | Even | tion** |         |      |     |
|                     | Patie | ts** |        |         |      |     |
|                     | nts** |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
|                     |       |      | **     | **Medic | **S  | **O |
|                     |       |      | None** | ation** | urge | the |
|                     |       |      |        |         | ry** | r^1 |
|                     |       |      | **Requ |         |      | ^** |
|                     |       |      | ired** |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
|                     |       |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Pain/Discomfort     | 37    | 44   | 15     | 15      | 8    | 14  |
|                     | (     |      |        |         |      |     |
|                     | 32.2) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Infection           | 36    | 41   | 0      | 16      | 33   | 3   |
|                     | (     |      |        |         |      |     |
|                     | 31.3) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Erosion             | 24    | 28   | 0      | 3       | 27   | 2   |
|                     | (     |      |        |         |      |     |
|                     | 20.9) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Recurring fecal     | 22    | 29   | 2      | 3       | 13   | 11  |
| incontinence        | (     |      |        |         |      |     |
|                     | 19.1) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Constipation        | 22    | 33   | 2      | 26      | 2    | 7   |
|                     | (     |      |        |         |      |     |
|                     | 19.1) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Impaction           | 21    | 27   | 2      | 7       | 3    | 17  |
|                     | (     |      |        |         |      |     |
|                     | 18.3) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Surgical injury     | 15    | 15   | 2      | 0       | 11   | 1   |
|                     | (     |      |        |         |      |     |
|                     | 13.0) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Wound problems      | 12    | 13   | 7      | 2       | 1    | 3   |
|                     | (     |      |        |         |      |     |
|                     | 10.4) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Mechanical          | 12    | 15   | 1      | 0       | 13   | 1   |
| malfunction         | (     |      |        |         |      |     |
|                     | 10.4) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Wound separation    | 10    | 10   | 4      | 4       | 1    | 2   |
|                     | (8.7) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Difficult           | 10    | 13   | 1      | 5       | 1    | 8   |
| evacuation          | (8.7) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Rectal bleeding     | 9     | 9    | 5      | 1       | 2    | 1   |
|                     | (7.8) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Edema               | 9     | 10   | 3      | 3       | 4    | 2   |
|                     | (7.8) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Erythema            | 9     | 10   | 3      | 6       | 1    | 2   |
|                     | (7.8) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Fever               | 7     | 7    | 0      | 6       | 1    | 0   |
|                     | (6.1) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Anorectal condition | 7     | 8    | 1      | 0       | 1    | 6   |
|                     | (6.1) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Device migration    | 7     | 9    | 1      | 0       | 7    | 0   |
|                     | (6.1) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Device Fit          | 6     | 6    | 2      | 1       | 3    | 1   |
|                     | (5.2) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Device Function     | 6     | 7    | 0      | 0       | 0    | 7   |
|                     | (5.2) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Wound drainage      | 6     | 7    | 1      | 2       | 1    | 3   |
|                     | (5.2) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Gastrointestinal    | 5     | 6    | 1      | 1       | 2    | 2   |
| condition           | (4.3) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Diarrhea            | 5     | 7    | 2      | 1       | 0    | 4   |
|                     | (4.3) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Ecchymosis          | 4     | 4    | 3      | 0       | 0    | 1   |
|                     | (3.5) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Malposition         | 4     | 4    | 1      | 0       | 3    | 0   |
|                     | (3.5) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Device operation    | 3     | 3    | 0      | 0       | 0    | 3   |
| difficulty          | (2.6) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| Other ^2^           | 27    | 20   | 7      | 3       | 1    | 9   |
|                     | (     |      |        |         |      |     |
|                     | 23.5) |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+
| **Totals**          |       | **3  | **67** | **106** | **1  | *   |
|                     |       | 95** |        |         | 42** | *11 |
|                     |       |      |        |         |      | 7** |
+---------------------+-------+------+--------+---------+------+-----+
| ^1^Other            |       |      |        |         |      |     |
| interventions       |       |      |        |         |      |     |
| reported included:  |       |      |        |         |      |     |
| fluid added to pump |       |      |        |         |      |     |
| via septum (15),    |       |      |        |         |      |     |
| enemas (14),        |       |      |        |         |      |     |
| deactivation of     |       |      |        |         |      |     |
| device (13),        |       |      |        |         |      |     |
| patient education   |       |      |        |         |      |     |
| (11),               |       |      |        |         |      |     |
| hospitalization     |       |      |        |         |      |     |
| (9). There were 18  |       |      |        |         |      |     |
| reports of an       |       |      |        |         |      |     |
| unspecified "other" |       |      |        |         |      |     |
| intervention.       |       |      |        |         |      |     |
|                     |       |      |        |         |      |     |
| ^2^Other adverse    |       |      |        |         |      |     |
| events included     |       |      |        |         |      |     |
| abscess (2),        |       |      |        |         |      |     |
| difficult device    |       |      |        |         |      |     |
| activation (2),     |       |      |        |         |      |     |
| hematoma (2),       |       |      |        |         |      |     |
| intraoperative      |       |      |        |         |      |     |
| bleeding (2),       |       |      |        |         |      |     |
| seroma, urinary     |       |      |        |         |      |     |
| tract infection,    |       |      |        |         |      |     |
| acute renal         |       |      |        |         |      |     |
| failure, ankle      |       |      |        |         |      |     |
| pain, chest rash,   |       |      |        |         |      |     |
| decreased perianal  |       |      |        |         |      |     |
| sensation, hip      |       |      |        |         |      |     |
| ulcer,              |       |      |        |         |      |     |
| hyperglycemia       |       |      |        |         |      |     |
| secondary to        |       |      |        |         |      |     |
| infection, mild     |       |      |        |         |      |     |
| pancreatitis, night |       |      |        |         |      |     |
| sweats,             |       |      |        |         |      |     |
| osteomyelitis,      |       |      |        |         |      |     |
| patient             |       |      |        |         |      |     |
| dissatisfaction,    |       |      |        |         |      |     |
| patient falling,    |       |      |        |         |      |     |
| couldn't pump       |       |      |        |         |      |     |
| device, device      |       |      |        |         |      |     |
| locked, post-stoma  |       |      |        |         |      |     |
| takedown paralytic  |       |      |        |         |      |     |
| ileus, morphine     |       |      |        |         |      |     |
| reaction,           |       |      |        |         |      |     |
| respiratory         |       |      |        |         |      |     |
| distress, severe    |       |      |        |         |      |     |
| acute esophagitis,  |       |      |        |         |      |     |
| urinary retention   |       |      |        |         |      |     |
| (2), vaginal rash   |       |      |        |         |      |     |
| and weakness.       |       |      |        |         |      |     |
+---------------------+-------+------+--------+---------+------+-----+

V.  **DEVICE DESCRIPTION AND OPERATION**

The Acticon™ Neosphincter is an implantable, fluid filled, solid
silicone elastomer device used to treat severe fecal incontinence. The
Acticon Neosphincter consists of three interconnected components: an
occlusive cuff, a pressure-regulating balloon and a control pump with a
septum. The components are connected with color-coated, kink-resistant
silicone tubing. The occlusive cuff is available in multiple different
sizes (widths of 2.0 and 2.9cm and lengths ranging from 8.0-14.0cm). The
proper size is determined intra-operatively by the use of a cuff sizer.
The control pump is 1.2cm by 3.6cm and contains the valves needed to
transfer fluid to and from the cuff as well as a deactivation button,
squeeze bulb, and septum port for adding fluid post-operatively. The
pressure-regulating balloon is available in 4 different pressure ranges
(81-120cm H2O). Only the shell wall thickness differs in the available
balloon ranges. It is 4.1cm in diameter when filled with 40cc of fluid
and controls the amount of pressure exerted on the anal canal by the
occlusive cuff. AMS Quick Connect Sutureless Window Connectors and/or
Suture-Tie Connectors are used to connect the tubing components and are
included in an accessory kit. In addition, the accessory kit contains
disposable blunt needles, the disposable cuff sizer, and a locking ring
holder. An Acticon-specific tubing passer, used to route the tubing of
the components through the appropriate tissue planes during
implantation, is also required during the surgical procedure. A Quick
Connect assembly tool is available separately if the Quick Connect
Sutureless Window Connector System is to be used. Figure 1 shows the
device and its components.

![](media/image1.wmf)

#### Figure 1

#### The AMS Acticon Neosphincter

The device simulates normal anal sphincter function by allowing the anal
canal to open at the control of the patient. The occlusive cuff is
surgically implanted around a segment of the anal canal. The device
maintains continence in the patient by using the pressure of the fluid
filled cuff to occlude the anal canal circumferentially. To evacuate the
bowel, the patient squeezes and releases the pump mechanism, located in
the labium or scrotum, several times to move fluid from the cuff to the
pressure-regulating balloon implanted in the abdomen. This movement of
fluid empties and collapses the cuff, resulting in the release of the
compressive force around the anal canal. This allows the patient to
defecate. Residual pressure within the regulating balloon allows fluid
to flow back into the cuff, automatically re-pressurizing the occlusive
cuff within a few minutes. A patient may need to squeeze the pump more
than once to complete a bowel movement.

**VII. ALTERNATIVE PRACTICES AND TREATMENTS**

Fecal incontinence is the involuntary loss of flatus, liquid, or solid
stool and presents in a range of severity. Fecal incontinence is a
condition that can have distressing effects on a person's working life,
social life, and emotional well-being. Individuals who suffer from the
condition often alter their lifestyle to minimize the likelihood of
bowel accidents in public places. Fecal incontinence may result from a
variety of disease processes including injury to the anal sphincter from
obstetrical or surgical procedures, trauma, rectal prolapse,
neurological diseases or impairment, intestinal infection, fecal
impaction, and collagen vascular diseases.

The vast majority of cases of fecal incontinence are mild to moderate
and can be managed with medical interventions such as pharmacological
therapy and dietary modifications. In one subgroup of patients with
retained rectal sensation and the ability to voluntarily contract the
external anal sphincter, biofeedback may be successful in up to 90% of
those treated. Surgical repairs may benefit certain patients including
those with sphincter defects and rectal prolapse. Success rates for
these procedures may approach 70-90%.

For individuals with severe fecal incontinence who have failed medical
interventions and/or are not candidates for biofeedback or surgical
repair, the choices are limited.

Adynamic muscle transposition, an alternative surgical procedure, may be
used in patients where the anal sphincter is either denervated or
anatomically absent. It involves the transposition of a muscle, usually
the gracilis or gluteus maximus, to create a barrier to the passage of
stool. Success rates for this type of surgery vary greatly. Finally,
some patients are faced with a choice of permanent ostomy, a surgically
created passage to allow bodily wastes to be expelled from the body
through the abdominal wall.

VIII. **MARKETING HISTORY**

**Foreign Market Introduction**

A CE-mark for the Acticon was received in May of 1996. Limited marketing
of the Acticon Neosphincter in select European countries and Australia
began in July of 1996. In 1998 the device was introduced in other
markets including Brazil, Canada, China, Europe, and Taiwan. The Acticon
Neosphincter has not been withdrawn from marketing for any reason
related to lack of safety or effectiveness.

**Domestic Market Introduction**

Humanitarian Device Exemption approval was received in September of
1999. In accordance with HDE approval orders, including the need for IRB
approval, marketing of the Acticon Neosphincter at select centers in the
United States began in October 1999.

IX. **SUMMARY OF PRECLINICAL STUDIES**

**Materials Safety and Toxicology Testing**

The safety of the materials used in the Acticon Neosphincter were
evaluated through a testing program that included chemical analysis of
exhaustive extracts, infrared spectral analysis of surfaces having
direct tissue contact, and a series of *in vitro* and *in vivo*
biological studies. All biological non-clinical laboratory studies were
conducted in compliance with the Good Laboratory Practice Regulations.

*Chemical Analysis of Extractives*

Testing conducted on two other marketed devices manufactured by AMS, the
AMS Model 800 Artificial Urinary Sphincter (AUS) and the AMS Dynaflex
inflatable penile prosthesis were used to support safety of the Acticon
Neosphincter. These devices use the identical materials and the design
of the AUS is almost identical to the Acticon Neosphincter. Extractive
analysis identified compounds that may leach from the Acticon
Neosphincter and quantified the potential exposure to each extractive.
These included polydimethylsiloxanes of varying molecular weights (296
to \>150,000 daltons), water soluble silica (silicic acid),
formaldehyde, and traces of platinum and tin catalysts. For each
extractable compound known to produce some toxic or irritant effect(s)
the total potential exposure from an Acticon Neosphincter was shown to
be well below the exposures required to produce any observed effect
based on published toxicity data for each extractive. Exposure to
leachable components at the concentrations present in the Acticon
Neosphincter was determined not to be a significant health risk for
patients.

*Infrared Spectra Surface Analysis*

To document the principle chemical composition for each device component
which could have direct tissue contact, infrared spectra of the outer
device surfaces were collected using attenuated total reflectance
Fourier transform infrared spectroscopy. Testing showed that only
polydimethylsiloxane has direct tissue contact. No other materials or
unusual spectral features were detected.

*Biological Safety Tests*

Finished products were subject to the complete spectrum of biological
tests cited in the "Guidance for Manufacturers of Silicone Devices
Affected by Withdrawal of Dow Corning Silastic Materials (July 6,
1993)." This included tests for *in vitro* cytotoxicity, acute systemic
toxicity, intracutaneous irritation, sensitization, direct tissue
contact (intramuscular implantation for 14 and 90 days) and three
genetic toxicity tests.

Studies were also conducted in which substantial amounts of ground
silicone elastomer were implanted subcutaneously in Sprague Dawley rats.
The effects of the implanted material on the host system was evaluated.
The tests included an acute pharmacokinetic study (distribution and
excretion of silicones), testing for effects on the immunological system
(immunomodulation and adjuvanticity), and studies for sub-chronic and
chronic toxicity, reproductive effects, and oncogenicity.

Test results indicate that the materials used in the Acticon
Neosphincter do not produce localized or systemic toxic effects when
implanted.

**Mechanical Testing**

A risk analysis, including a failure modes and effects analysis (FMEA),
was used to identify safety and reliability attributes applicable to the
Acticon Neosphincter or its components. Bench testing was performed to
characterize the device components, attributes, and functions. All bench
testing was performed on finished, sterilized devices or components.

*Performance Characteristics Testing*

Performance characteristics of the device were evaluated by testing
samples for the following performance characteristics:

> Squeeze force versus fluid displacement
>
> Fluid displacement per pump stroke
>
> Prevention of spontaneous inflation or deflation
>
> Pump output pressure produced by pump squeeze force
>
> Pump bulb refill time
>
> Pump deactivation force and activation pressure
>
> Pump valve leakage and maximum back pressure
>
> Tubing kink resistance
>
> 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. Test results also indicated that device performance was not
affected by the sterilization method or accelerated aging.

*Reliability Testing*

Device reliability attributes were evaluated in bench testing by
subjecting samples to representative *in vivo* conditions, where
possible, and to a number of uses likely to exceed the number of uses
over the estimated life of the device. The following reliability testing
was performed:

> Cuff deflation/inflation cycling
>
> Pump cycling
>
> Balloon inflation/deflation cycling
>
> Pump cycling and septum access
>
> Cuff fold wear resistance life cycling
>
> Prosthesis 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 attributes were evaluated by subjecting test samples
under representative *in vivo* conditions, where possible, and for a
number of uses likely to exceed the number of uses over the estimated
life of the prosthesis for the following strength attribute analysis:

> Cuff maximum pressure and expansion
>
> Cuff leakage or unbuckling under pressure
>
> Connector strength
>
> Tubing burst/leak pressure
>
> Connector/component leak pressure
>
> Subassembly bond strength
>
> Prosthesis material strength

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

**Shelf Life Testing**

Shelf life was determined to be equivalent to the shelf life of the AMS
inflatable penile prostheses products (700, Ultrex, CX, Ambicor) and the
AMS 800 artificial urinary sphincter. The three product lines use the
same materials for packaging. An accelerated aging study was performed
on the package configuration and showed the packaging would provide
physical protection and a sterile barrier for a 5-year shelf life with a
2-year safety margin. The Acticon Neosphinter is labeled with a "use
before date" which is 5 years from the date of manufacture.

**Sterilization**

The components of the Acticon Neosphincter Prosthesis are sterilized
using either steam or ethylene oxide. The sterilization protocols are
adequate. The identical methods for sterilization are used with the
American Medical Systems Artificial Urinary Sphincter.

The pressure regulating balloon is sterilized at a contract
sterilization facility, using ethylene oxide, to a sterility assurance
level of 10^-6^. American Medical Systems uses steam to sterilize the
cuff and pump at their facility in Minnetonka, Minneasota, to a
sterility assurance level of 10^-6^.

Two components of the system the AMS Quick Connect Assembly Tool and AMS
Tubing Passers are shipped to the user nonsterile. The AMS Quick Connect
Assembly Tool and Tubing Passers are reusable components used during
surgical placement of the system. They are shipped to the user
nonsterile in steam sterilization packages ready for hospital
sterilization.

X.  **SUMMARY OF CLINICAL STUDIES**

Two clinical studies conducted in the United States by American Medical
Systems, are described in the PMA to support the safety and
effectiveness of the Acticon Neosphincter. The first study (IDE
#G880037) began in August 1988 and was closed in April 1995. The second
study (IDE #G960116) started enrolling subjects in February 1997 and was
closed in December of 1999.

**[IDE #G880037]{.underline}**

This study was a multi-center, prospective pilot study of the Artificial
Bowel Sphincter (ABS), an earlier version of the Acticon Neosphincter
which was adapted from the AMS 800 Urinary Sphincter. Patients selected
for the study demonstrated fecal incontinence unresponsive or unlikely
to respond to accepted medical or surgical alternatives. The objectives
of this study were to:

demonstrate that the device could be implanted without adverse sequelae;

demonstrate that the device provided an acceptable level of continence;

demonstrate that the anticipated adverse events had a low incidence and

could be managed without long-term sequelae; and

demonstrate that there were no unanticipated adverse responses
associated

with the device.

A total of 21 patients (11 females and 10 males) ranging in age from
15-68 years were enrolled at 3 different sites for this study. The
etiologies of incontinence are provided in Table 2.

**Table 2: Etiology of Incontinence (IDE #G880037)**

  -------------------------------------- --------------------- -------------
  **Etiology of Incontinence**           **Number of           **Percent**
                                         Patients**            

  Major Trauma                           6                     28.6

  Birthing Injury                        5                     23.8

  Imperforate Anus                       3                     14.2

  Spinal Cord Tumor                      2                     9.5

  Laminectomies                          2                     9.5

  Spina Bifida                           1                     4.8

  Myasthenia Gravis                      1                     4.8

  Prolapse Intervertebral Disc           1                     4.8

  Total Patients                         21                    100
  -------------------------------------- --------------------- -------------

Adverse events that occurred during the pilot study included:

infection (5 patients);

mechanical malfunction (5 patients with 2 patients having multiple

problems); and

pain (2 patients).

Device revisions which included repositioning, replacing or removing
specific components or the entire device, were required in 9 of the 21
patients (43%) including all 5 with mechanical malfunction and 4 of the
5 patients with infection. One case of infection resolved with
antibiotics alone. Five of the 21 patients (24%) required permanent
device explantation (2 of the 5 patients with malfunction and 3 of the 5
with infection).

Effectiveness outcomes were based on manometry testing and continence
diaries. Patient follow-up ranged from 6 to 76 months. The 16 patients
who did not require device explantation were considered in the analysis
of effectiveness. The investigators reported that 64% (10/16) of these
patients achieved complete continence to liquid and solid stool. An
additional 18% (3/16) achieved continence to solid stool but experienced
occasional leakage of liquid stool. When all patients enrolled in the
study are taken into account on an intent to treat basis, 62% (13/21)
demonstrated either improvement or resolution of their fecal
incontinence.

**Study Conclusions**

Based on the results of this study (IDE #G880037) the sponsor conducted
additional product development which included modifications to the
device in preparation for a modified and expanded pivotal clinical
trial. Compared to the ABS, the newer Acticon Neosphincter was designed
with:

a longer reinforced cuff;

a larger (40cc) pressure regulating balloon; and

a septum as part of the control pump to add fluid to the system post-

operatively.

**[IDE #G960116]{.underline}**

**Study Design**

This second, larger pivotal study was a multi-center, prospective,
non-randomized trial in which each subject served as his or her own
control. Patients at least 18 years of age with severe incontinence
without regard to etiology were considered for implantation of the
device. Severe fecal incontinence, as defined in the protocol, was the
involuntary loss of liquid or solid stool on a weekly or more frequent
basis. The main objectives of the study were to:

> demonstrate that the Acticon Neosphincter could be surgically
> implanted without serious adverse sequelae;
>
> demonstrate that the Acticon Neosphincter provided an acceptable level
> of continence as determined through the use of the Fecal Incontinence
> Scoring System (FISS) Questionnaire; and
>
> report the adverse events associated with the implantation of the
> Acticon Neosphincter and to demonstrate that the events could be
> managed without serious sequelae.

**Patient Selection**

**Patient Inclusion Criteria**

1.  Patient had fecal incontinence for at least 6 months.

2.  Patient failed at least one non-surgical treatment for incontinence.

3.  Patient had a FISS incontinence score of at least 88.

4.  Patient was at least 18 years of age.

5.  Patient was an acceptable risk for surgery and anesthesia.

6.  Patient was willing to give informed consent.

7.  Patient was willing to return for follow-up visits.

8.  Patient was able to understand and complete questionnaires.

9.  Patient's life expectancy was greater than 2 years.

10. Patient had sufficient dexterity and mental capacity to operate the
    device.

**Patient Exclusion Criteria**

1.  Patient had a FISS score less than 88.

2.  Patient had irritable bowel syndrome as their only cause of
    incontinence.

3.  Patient had inflammatory bowel disease.

4.  Patient had active pelvis sepsis.

5.  Patient was pregnant.

6.  Patient had a history of extensive pelvic radiation that would
    compromise the anal canal.

7.  Patient had a scarred and fragile perineum.

8.  Patient had engaged in anal receptive intercourse.

9.  Patient had enrolled in another study involving investigational
    products.

**Patient Demographics and Etiology**

A total of 115 patients were enrolled at 19 different sites in the
United States (13), Canada (3), France (2), and Spain(1). This included
86 females (75%) and 29 males (25%). The average age at enrollment for
females was 53, males 36 (p=0.0001, females versus males), and overall,
47. Caucasians comprised 80% of those enrolled, Hispanics 4%,
African-Americans 3%, and Asians 2%. The races of 11 European patients
were not recorded. The etiologies of incontinence are shown in Table 3.

**TABLE 3- Distribution of Patients by Etiology**

+----------------------------------+---------------+-------------------+
| **Etiology of Fecal              | **Number of   | **Percent (%)**   |
| Incontinence**                   | Patients**    |                   |
+----------------------------------+---------------+-------------------+
| Obstetric Trauma                 | 34            | 29.57             |
+----------------------------------+---------------+-------------------+
| Neurological                     | 23            | 20.00             |
+----------------------------------+---------------+-------------------+
| Congenital Abnormality           | 23            | 20.00             |
+----------------------------------+---------------+-------------------+
| Anorectal Trauma                 | 21            | 18.26             |
+----------------------------------+---------------+-------------------+
| Other                            | 14            | 12.17             |
+----------------------------------+---------------+-------------------+
| # Total Patients                 | **115**       | **100**           |
+----------------------------------+---------------+-------------------+

Other includes: rectal prolapse (3), idiopathic (3), radiation (1),
surgical (3),

scleroderma (1), traumatic defecation (1), musculoskeletal (1), and anal
canal

squamous cell carcinoma (1)

**Pre-Implant Procedures and Treatment**

All patients had undergone, and failed, at least one traditional
non-surgical treatment for fecal incontinence prior to receiving the
Acticon Neosphincter. In addition, many of the patients had also
undergone a surgical procedure prior to implantation. These therapies
are shown in Table 4.

**TABLE 4**

**Distribution of Patients by Previous Treatment for Fecal
Incontinence**

+-------------------------------------------+-------------+------------+
| **Type of Previous Treatment**            | **Total     | ####### P  |
|                                           | Patients**  | ercent (%) |
+-------------------------------------------+-------------+------------+
| *Management:*                             |             |            |
+-------------------------------------------+-------------+------------+
| Bowel Management                          | 83          | 72.2       |
+-------------------------------------------+-------------+------------+
| Biofeedback                               | 25          | 21.7       |
+-------------------------------------------+-------------+------------+
| *Surgical Treatment:*                     |             |            |
+-------------------------------------------+-------------+------------+
| Sphincteroplasty                          | 38          | 33.0       |
+-------------------------------------------+-------------+------------+
| Stoma                                     | 30          | 26.1       |
+-------------------------------------------+-------------+------------+
| Rectal Prolapse Repair                    | 12          | 10.4       |
+-------------------------------------------+-------------+------------+
| Gracilis Muscle Transposition             | 5           | 4.3        |
| (stimulated)                              |             |            |
+-------------------------------------------+-------------+------------+
| Gracilis Muscle Transposition             | 2           | 1.7        |
| (unstimulated)                            |             |            |
+-------------------------------------------+-------------+------------+
| Postanal Repair                           | 2           | 1.7        |
+-------------------------------------------+-------------+------------+
| Other                                     | 29          | 25.2       |
+-------------------------------------------+-------------+------------+

> Patients with multiple types of treatments were counted more than
> once. Therefore, the total number of
>
> patients reported for all etiologies is greater than the actual number
> of patients enrolled. Percentages have been calculated based on the
> actual number of patients enrolled and therefore also add up to more
> than 100%. Percentages are percentage of patients having had the
> specific type of treatment. However, some patients had more that one
> procedure of the same type, and these are captured under the "other"
> category. Other includes: Second sphincteroplasty (10), silastic sling
> (3), repair of imperforate anus (4), revised colostomy (3), repeated
> rectal prolapse repair (2), repair neosphincter and second gracilis
> muscle wrap, posterior sagioplasty/vaginal anoplasty, abdominal
> exploratory/rectopexy and levatorplasty, posterior colporrhaphy/repair
> perineal body, 4-V advancement flap, neorectum, vaginal and anal
> reconstruction.

**Follow-up**

Two weeks after implantation, patients were seen for evaluation of the
surgical wound. The patients returned to their physician's office 6-8
weeks after implantation for activation of the device. Those patients
with pre-existing ostomies underwent stoma take-down. Patients were then
followed at 6 and 12 months. At the 6-month follow-up patients underwent
a history/physical examination and anorectal manometry. In addition, the
FISS and Fecal Incontinence quality of life questionnaires were
completed by the patient. At 12 months the patients had these same
evaluations as well as an endoanal ultrasound and the Health Status
Quality of Life questionnaire.

**Patient Accountability**

One hundred and fifteen (115) patients were enrolled in the study and
112 underwent device implantation. For one of the three patients who
were enrolled but not implanted with the device, a large enough cuff was
not available. A second patient was found to have megarectum with stool
impaction at the time of surgery and was not implanted. A third patient
experienced perforation at the time of surgery and elected not to
continue in the study. Table 5 shows the follow-up compliance for the
112 patients implanted with the device.

######## TABLE 5 -Follow-up Compliance

+-------------------------------+------------+------------+-----------+
| **Patient Status**            | **Ac       | **6        | **1       |
|                               | tivation** | Months**   | Year**    |
+-------------------------------+------------+------------+-----------+
| > Follow-up performed         | 98         | 73         | 69        |
+-------------------------------+------------+------------+-----------+
| > Due for follow-up           | 0          | 0          | 1         |
+-------------------------------+------------+------------+-----------+
| > Missed follow-up            | 1          | 6          | 5         |
+-------------------------------+------------+------------+-----------+
| > Not eligible for follow-up  | 0          | 0          | 0         |
+-------------------------------+------------+------------+-----------+
| > Explanted                   | 13         | 31         | 34        |
+-------------------------------+------------+------------+-----------+
| > Deceased                    | 0          | 0          | 0         |
+-------------------------------+------------+------------+-----------+
| > Lost to follow-up           | 0          | 2          | 3         |
+-------------------------------+------------+------------+-----------+
| ########                      |            |            |           |
+-------------------------------+------------+------------+-----------+
| ######## Total Patients       | **112**    | **112**    | **112**   |
+-------------------------------+------------+------------+-----------+

**Endpoints**

Change in incontinence symptoms after one year of treatment as
determined by the Fecal Incontinence Scoring System (FISS) was used as
the study's primary effectiveness endpoint. Device effectiveness was
assessed by analyzing the difference between the pre-implant FISS score
and the score at 12 months post-implantation. This scale was developed
in part by the sponsor and has been validated by Vaizey *et al* (*Gut*
1999; 44:77-80). The FISS is a self-administered, 5-item questionnaire
which assesses the frequency and severity of the patient's incontinence
symptoms. Four questions assess how often in the proceeding 4 weeks a
patient has experienced leakage of

gas;

seepage/soiling;

liquid stool; and

solid stool.

The fifth question assesses the effect of accidental bowel leakage on
the patient's lifestyle. Each possible response had a unique score
assigned to it. A sample of the FISS questionnaire is shown in Figure 2.

Figure 2. Fecal Incontinence Scoring System Questionnaire

![](media/image2.png)

The final FISS score is obtained by taking the highest score from the
first 4 questions and adding the score from the 5^th^ question. In the
sample questionnaire in Figure 2, a total score of 88 would be recorded
for that patient. The correlation of FISS scores to bowel activity is
shown in Table 6.

Table 6: Fecal Incontinence (FI) Score Definitions

+---------------------------+------------------------------------------+
| **FI Value**              | **Definition**                           |
+---------------------------+------------------------------------------+
| > 0-60                    | > Continent to solid and liquids         |
+---------------------------+------------------------------------------+
| > 61-72                   | > Incontinent \< monthly                 |
+---------------------------+------------------------------------------+
| > 73-84                   | > Incontinent \> monthly                 |
+---------------------------+------------------------------------------+
| > 85-96                   | > Incontinent \>weekly                   |
+---------------------------+------------------------------------------+
| > 97-108                  | > Incontinent daily                      |
+---------------------------+------------------------------------------+
| > 109-120                 | > Incontinent \>daily                    |
+---------------------------+------------------------------------------+

A patient was considered to have a clinically successful outcome at the
one-year follow-up point if he or she had a score reduction of
[\>]{.underline} 24 points compared to baseline (pre-implant).

Secondary endpoints were also evaluated pre and 12 months
post-implantation to assess effectiveness, safety and impact on patient
quality of life. These endpoints included:

all adverse device events;

mean resting sphincter pressures as determined by anorectal manometry;
and

alterations in quality of life as measured by two separate
questionnaires, one

> addressing specific incontinence issues (Fecal Incontinence Quality of
> Life) and the other general health (Health Status Questionnaire).

**Effectiveness**

**Primary Effectiveness Endpoint:** Fecal Incontinence Scoring System
(FISS)

Of the 115 patients enrolled in the study, pre-implant FISS scores were
not attainable in 14 patients with a pre-existing stoma. For the
remaining 101 patients, the mean score prior to implantation was 106
(range 71-120). Thirty-eight (38) patients (33%) scored in the most
severe category (score 109-120) prior to implantation with 23 (20%)
having the maximal score of 120. Thirty-five patients (30%) had
pre-implant scores of 97-108, and the remaining patients had either
scores of 96 or less (28 patients).

For 63 patients, FISS scores had been collected at both pre-implantation
and at the 12-month follow-up. The mean 12-month score for this set of
patients was 48 compared to 105 at baseline (p\<0.0001), representing an
average reduction in score of 57 points. Of these 63 patients, 54
(85.7%) had a reduction in FISS score of [\>]{.underline}24 points at
the 12 month follow-up and were therefore considered to have had a
clinically successful outcome. At the 12-month follow-up, females had a
greater drop in FISS score (58 points) compared to males (50 points).
This difference was statistically significant (p\<0.05), but the
clinical significance is uncertain as the number of males enrolled was
small and both groups on average showed reductions of more than twice
that required to define clinical success. No other significant
differences were noted among other subgroups including age and etiology
of incontinence. In addition to these 63 patients, 6 patients with
pre-existing stomas completed 12 months of follow-up bringing the total
of patients with 12-month FISS scores to 69. Of these 69 patients:

7 (10%) had achieved total continence (score of zero);

11 (16%) were incontinent to gas only; and

29 (43%) reported seepage or rare incontinence to liquid or solid stool

**Intent to Treat Analysis**

Six patients with a pre-existing stoma completed follow-up and had
12-month FISS scores available. To be included in an intent to treat
analysis, these 6 patients had a pre-implant FISS score of 106 (the
average for the 101 non-stoma patients) assigned to them. Using this
assumption, 5 of these 6 stoma patients had a successful outcome at 12
months as defined by a [\>]{.underline}24-point drop in FISS score.

A total of 34 patients had the Acticon device entirely explanted before
reaching their 12-month follow-up and were considered treatment failures
in the intent to treat analysis. In addition, the three patients with
aborted implantation, the 6 patients with missing 12-month data and the
3 patients lost to follow-up were also considered treatment failures.

By an intent to treat analysis which accounts for all enrolled patients,
the clinical success rate for the Acticon Neosphincter based on 12-month
FISS scores was 51.3% (59 of 115).

**Secondary Effectiveness Endpoint:** Anorectal Manometry.

Mean anal sphincter resting pressures were evaluated by anorectal
manometry prior to implantation and at the 6 and 12-month follow-up
visits. Results of these manometry studies are shown in Table 7.

######## TABLE 7 -Anorectal Manometry Resting Pressures (mmHg)

+-----------------+------------+-----------+-------------+------------+
|                 | **Pre      | **Act     | **6 Month   | **12 Month |
|                 | -Implant** | ivation** | Post        | Post       |
|                 |            |           | A           | Ac         |
|                 | *          | *         | ctivation** | tivation** |
|                 | *(n=106)** | *(n=73)** |             |            |
|                 |            |           | **(n=61)**  | **(n=53)** |
+-----------------+------------+-----------+-------------+------------+
| > **Mean**      | 26         | 47        | 46          | 45         |
+-----------------+------------+-----------+-------------+------------+
| > **Minimum**   | 0          | 8         | 12          | 14         |
+-----------------+------------+-----------+-------------+------------+
| > **Maximum**   | 70         | 78        | 80          | 77         |
+-----------------+------------+-----------+-------------+------------+
| > **Standard    | 15         | 17        | 16          | 16         |
| > Deviation**   |            |           |             |            |
+-----------------+------------+-----------+-------------+------------+

There was a significant difference (p\<0.0001) in mean resting pressures
between pre-implant and 12-month follow-up. In addition, the data
suggested a statistically significant correlation between lower FISS
scores and higher mean resting pressures at 12 months (correlation =
-0.38, p = 0.0039).

**Secondary Effectiveness Endpoint:** Fecal Incontinence QOL (FIQOL)
Questionnaire.

The Fecal Incontinence Quality of Life Questionnaire is a psychometric
evaluation which assesses the impact of accidental bowel leakage on a
variety of activities and feelings. The 39-item questionnaire was
self-administered to the patients prior to implantation and at the 6 and
12-month follow-up visits. For each feeling or activity, the patients
were asked to respond with one of the following 5 choices:

Most of the Time OR Strongly agree;

Some of the Time OR Somewhat Agree;

A Little of the Time OR Somewhat Disagree;

None of the Time OR Strongly Disagree; or

Does Not Apply

Sixty-seven (67) patients completed the FIQOL questionnaire at their 12
month follow-up visit. The percentage of patients responding "Most of
the time" or "Strongly agree" at baseline and at the 12 month follow-up
for the most common feelings or activities are shown in Table 8.

**Table 8. Fecal Incontinence Quality of Life**

**[Feeling or Activity]{.underline} Pre-Implant 12 months**

**[(n=113)]{.underline} [(n=67)]{.underline}**

# Feel I have no control over bowels 89% 9%

# Worry about accidents 86% 22%

# Alter activities to be near bathroom 81% 33%

Worry about being embarrassed 80% 25%

Bowel accidents are always on my mind 78% 25%

# Use pads 77% 39%

Worry about others smelling stool 76% 19%

Locate bathrooms when someplace new 76% 34%

My life is more difficult 70% 15%

# Afraid to wear light colored clothing 69% 24%

Cannot do things I want to 68% 16%

Feel ashamed 66% 18%

Plan schedule around bowels 65% 21%

**Secondary Effectiveness Endpoint:** Health Status Questionnaire (HSQ
2.0).

The Health Status Questionnaire (HSQ 2.0) was developed by the Health
Outcomes Institute and was self-administered by the patients prior to
implantation and at the 6 and 12 month follow-up intervals. This was
derived from the MOS-20 questionnaire which was validated as part of the
Rand Corporation's Medical Outcomes Study. Three questions regarding
depression were added for this study. The questionnaire consists of 8
scales/domains related to general well-being. Each scale produced
possible scores from zero to 100, with 100 representing ideal
functioning. Data was available on 48 patients who had completed an HSQ
prior to implantation and at the 12-month follow-up. The mean overall
score increased from 457 at baseline to 555 (p\<0.0001) at 12 months. Of
the 8 distinct scales, 6 showed statistically significant improvement at
12 months. These results are summarized in Table 9.

######## TABLE 9 -Health Status Questionnaire 2.0

+----------------------------+------------------------+----------------+
| **Scale**                  | **Mean pre-implant     | **p-value**    |
|                            | to**                   |                |
|                            |                        |                |
|                            | **12-mos. (n=48)**     |                |
+----------------------------+------------------------+----------------+
| Health Perception          | 9.16                   | 0.0011         |
+----------------------------+------------------------+----------------+
| Physical Functioning       | 16.62                  | \<0.0001       |
+----------------------------+------------------------+----------------+
| Role Limitations/Physical  | 22.02                  | 0.0019         |
| Health                     |                        |                |
+----------------------------+------------------------+----------------+
| Role Limitations/Emotional | 10.34                  | 0.1232         |
| Problems                   |                        |                |
+----------------------------+------------------------+----------------+
| Social Functioning         | 18.02                  | \<0.0001       |
+----------------------------+------------------------+----------------+
| Mental Health              | 13.17                  | 0.0002         |
+----------------------------+------------------------+----------------+
| Bodily Pain                | 6.92                   | 0.1610         |
+----------------------------+------------------------+----------------+
| Energy/Fatigue             | 7.13                   | 0.0400         |
+----------------------------+------------------------+----------------+
| Overall HSQ                | 97.94                  | \<0.0001       |
+----------------------------+------------------------+----------------+

**Secondary Effectiveness Endpoint:** Safety and Adverse Events

No deaths or life-threatening conditions were reported during the
clinical trial.

**Adverse Events**

Table 1 (Adverse Events Of The Device On Health, page 6) lists the
device-related adverse events observed during the pivotal clinical study
and the methods of intervention which were required. A total of 395
device-related adverse events occurred in 102 patients. These events are
discussed in further detail below.

[Surgical Injury]{.underline}

Fifteen (15) adverse events were reported to occur at the time of
implant surgery. These included:

perforation to the vagina and/or rectum (12 cases);

perforation of the bladder (2); and

separation of deactivation plug from tubing in the subcutaneous tissue
(1).

All surgical injuries encountered at the time of the original implant
procedure resolved without any long-term sequelae.

[Infection]{.underline}

Thirty-six patients (31%) experienced 41 device-related infectious
adverse events during the course of the clinical study. Eleven separate
infectious events in 8 patients resolved with antibiotics alone. The
remaining 30 infectious complications, which occurred in 28 different
patients, required surgical device revision to correct (See **Device
Revisions** below).

[Erosion]{.underline}

Erosion of the Acticon Neosphincter device into or through surrounding
tissue occurred 28 times in 24 different patients (21% of those
enrolled). The more common locations for erosion included:

cuff eroding to the rectum;

cuff eroding to the perineum; or

pump eroding through the skin of the labia or scrotom.

Although not seen during the course of the clinical trial, the
possibility for erosion of the pressure-regulating balloon to the
bladder or bowel also exists. Twenty-seven of the erosion events
required a revision surgery to correct (See **Device Revisions** below).

[Change in Bowel Habits]{.underline}

Following implantation with the Acticon Neosphincter, 22 patients (19%)
experienced difficulty with constipation and 21 patients (18%)
experienced at least one episode of fecal impaction. The majority of
these adverse events (94% and 89% respectively) improved or were
resolved with non-surgical management. In addition, 22 patients (19%)
also noted a return or worsening of fecal incontinence after an initial
improvement in their symptoms. Most of these patients were managed
conservatively as well.

[Mechanical Malfunction]{.underline}

Mechanical malfunctions occurred in approximately 10% of patients
enrolled in the study and included difficulties with the cuff opening or
leaking and pump malfunction. The majority of these occurred early in
the course of the study. Ninety-two percent (92%) of these mechanical
malfunctions required further surgery to correct.

[Migration]{.underline}

Device migrations, mainly involving the control pump, occurred in 6% of
patients implanted with the device. Eight-nine percent (89%) of these
events required surgical intervention.

**Surgical Interventions**

A total of 101 surgeries were performed following the initial device
implant in 60 patients to resolve 142 specific device-related adverse
events. In some cases, multiple adverse events may have been resolved by
a single surgery. Of the 101 surgeries, 81 consisted of device
revisions.

**Device Revisions**

A revision was defined as any surgical procedure involving the Acticon
Neosphincter subsequent to the original implant procedure. During
revision, one or more of the device components may have been
repositioned, removed, and/or replaced. A total of 81 device revisions
were required in 56 of the 112 implanted patients, giving a revision
rate of 50%. Of these 56 patients:

38 (34% of implanted patients) required 1 revision surgery;

14 (13%) required 2 revision surgeries;

1 (1%) required 3 revision surgeries; and

3 (3%) required 4 revision surgeries

The indications for revision are shown in Table 10. Patients may have
had multiple occurrences of the same event type. In addition, more than
one reason may have existed for each revision. For example, infection
and erosion occurred simultaneously as an indication for revision in 13
cases.

**Table 10: Device Revisions from Acticon Neosphincter Clinical Study**

+---------------------------+-------------+---------------+-----------+
| **Reasons for revision    | **Number of | **Number of   | **% of    |
| ^2^**                     | Events^1^** | Patients**    | p         |
|                           |             |               | atients** |
|                           |             |               |           |
|                           |             |               | **        |
|                           |             |               | (n=112)** |
+---------------------------+-------------+---------------+-----------+
| Infection                 | > 30        | > 28          | > 25.0    |
+---------------------------+-------------+---------------+-----------+
| Erosion                   | > 27        | > 24          | > 21.4    |
+---------------------------+-------------+---------------+-----------+
| Malfunction               | > 13        | > 11          | > 9.8     |
+---------------------------+-------------+---------------+-----------+
| Recurring Incontinence    | > 11        | > 10          | > 8.9     |
+---------------------------+-------------+---------------+-----------+
| Migration                 | > 7         | > 6           | > 5.4     |
+---------------------------+-------------+---------------+-----------+
| Pain                      | > 6         | > 6           | > 5.4     |
+---------------------------+-------------+---------------+-----------+
| Patient Dissatisfaction   | > 4         | > 4           | > 3.6     |
+---------------------------+-------------+---------------+-----------+
| Malposition               | > 3         | > 3           | > 2.7     |
+---------------------------+-------------+---------------+-----------+
| Other^1^                  | > 13        | > 13          | > 11.6    |
+---------------------------+-------------+---------------+-----------+
| **Total:**                | > 81        | > 56          | > 50.0    |
+---------------------------+-------------+---------------+-----------+

^1^ Other reasons for revision included replacing previously removed
cuff (2), incision open (1), two stage device removal (2), cuff opened
(3), cellulitis/erosion of the peritoneal skin (1), improperly sized
cuff (1), constipation (2) and ano-urethral communication (1)

Ten patients who underwent one or more revision surgeries prior to the
12 month visit had functional devices at 12 months. Eight (8) of these
10 patients were considered clinical successes by FISS Scores.

[Infection and Revision]{.underline}

Twenty-five percent (25%) of patients implanted with the Acticon
Neosphincter experienced at least one infectious complication which
required surgical revision to correct. Of the infectious events which
eventually led to a revision procedure, 32% occurred within 30 days, 43%
within 60 days, and 54% within 90 days of the original implantation
surgery. During the course of the pivotal study, a revised and stringent
peri-operative antibiotic regimen was instituted when it was recognized
that infectious complications were the leading cause of surgical
revisions. Only 2 of the 16 patients (12.5%) who received this regimen
developed an infectious complication that required a revision procedure.

[Erosion and Revision]{.underline}

Twenty-four implanted patients (21.4%) experienced at least one erosion
event and a total of 27 revision surgeries were required to correct the
event. The locations of these erosions included:

Cuff erosion to the rectum (12 cases)

Cuff erosion to the perineum (10 cases)

Pump erosion through the skin of the scrotom or labium (4 cases)

Tubing erosion (1 case)

**Device Explantations**

An explantation was the surgical removal of the entire prosthesis after
the original implantation. A total of 34 patients (30% of those
implanted) had the Acticon Neosphincter explanted within one year of
implantation. Four (4) patients had the device explanted twice. The
average time from implantation to device explant in these patients was
4.2 months, however 38% (13/34) occurred prior to the activation
follow-up which was scheduled to occur 6-8 weeks after implantation and
91% (31/34) occurred within the first six months. Infection and/or
erosion were the indication(s) for device removal in 92% (35/38) of the
cases as shown in Table 11.

**Table 11:Device Explants from Acticon Neosphincter Clinical Study**

  ------------------------------------------------ ----------------------
  **Reasons for explant**                          **Number of
                                                   Events^1^**

  Infection                                        12

  Infection and erosion                            12

  Erosion                                          11

  Recurring Incontinence and pain                  2

  Ano-urethral communication                       1

  **Total Explants**                               **38**
  ------------------------------------------------ ----------------------

> ^1^Patients may have multiple occurrences of the same event type.

Seven of the 34 patients who required device explantation were
considered candidates for future re-implantation.

**International Marketing Surveillance**

According to the AMS Patient Information Form (PIF) database, 460
Acticon Neosphincters were implanted worldwide from May 1996 through
January 2001. The PIF is a form which is completed by the hospital at
the time of revision surgery and is *encouraged* by the sponsor to be
returned but not required. During this time period, 119 revisions were
reported in 94 patients following the original implant of the device.
Reasons for revision were recorded for 85 of these procedures and
included fluid loss (18), erosion (16), infection (15) and recurring
incontinence (14).

**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.

Results from the pivotal clinical trial indicate that slightly over
one-half (51.3%) of all patients who were implanted with the Acticon
Neosphincter for severe fecal incontinence had a resolution or
clinically significant reduction in their symptoms after one year. For
the subset of patients who were able to maintain a functional device for
12 months, approximately 85% had meaningful improvements in their
incontinence. In addition, quality of life measures showed improvement
in many of these latter patients. A majority of the patients implanted
experienced at least one device-related adverse event. Besides pain, the
two most common adverse events were infection (31% of implanted
patients) and device erosion (21%). Surgical intervention was required
to address 36% of these adverse events. Half (50%) of the implanted
patients required at least one additional surgical device revision after
the original implantation procedure and 30% required total device
explantation due to adverse events.

XII. **PANEL RECOMMENDATIONS**

The PMA was referred to the Gastroenterology and Urology Devices
Advisory Panel for review and recommendations on August 17^th^, 2001.
The panel recommended 7-1 that the application be approved subject to
submission to, and approval by, the Center for Devices and Radiological
Health (CDRH) of revised physician and patient labeling, revised
indications for use (for patients 18 and older), a formal physician
training program, and an agreement to conduct a 12-month post-market
follow-up study of those patients already enrolled in the pivotal
clinical trial. The panel recommended that patients under the age of 18
continue to be evaluated and receive the device, if clinically
indicated, under HDE provisions.

XIII. **CDRH DECSISION**

CDRH concurred with the Panel's recommendations. The applicant addressed
all issues raised by the Panel and CDRH. Based on the information
provided in the PMA, CDRH has determined that the Acticon Neosphincter
is safe and effective for the indication of treatment of severe fecal
incontinence in males and females eighteen years and older who have
failed, or are not candidates for, less invasive forms of restorative
therapy. FDA inspection of the manufacturing facilities determined that
the applicant was in compliance with the Quality Systems Regulation
{21CFR820}.

XIV. **APPROVAL SPECIFICATIONS**

**Professional Labeling**.

Acticon Neosphincter, Package Insert

Acticon Neosphincter Operating Room Manual

**Patient Labeling**

Acticon Neosphincter Patient Information Brochure

**Hazards to Health from Use of the Device**

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

**Post-approval Requirements and Restrictions**

See approval order