**SUMMARY OF SAFETY AND EFFECTIVENESS DATA**

I.  **GENERAL INFORMATION\
    \
    **DEVICE GENERIC NAME: Absorbable Adhesion Barrier\
    \
    DEVICE TRADE NAME: GYNECARE INTERGEL Adhesion

> Prevention Solution
>
> > APPLICANT: Lifecore Biomedical, Inc.
>
> 3515 Lyman Boulevard
>
> Chaska, MN 55318-3051
>
> PREMARKET APPROVAL P990015
>
> APPLICATION (PMA):

DATES OF PANEL

RECOMMENDATIONS: January 12, 2000 & September 6, 2001

> DATE OF GMP INSPECTION: December 28, 1999 & January 14, 2000
>
> DATE OF NOTICE OF APPROVAL
>
> OF APPLICATION: November 16, 2001
>
> EXPEDITED REVIEW: Expedited processing was authorized on April 26,
> 1999, based on the potential of GYNECARE INTERGEL to provide a
> specific public health benefit by reducing the incidence, extent, and
> severity of newly formed adhesions.

II. **INTENDED USE/INDICATIONS**

**\
**GYNECARE INTERGEL Solution is indicated for use in patients undergoing
open, conservative gynecologic surgery as an adjunct to good surgical
technique to reduce post-surgical adhesions. GYNECARE INTERGEL Solution
is also intended to reduce the likelihood of developing moderate or
severe postoperative adnexal adhesions in these patients.

**III. DEVICE DESCRIPTION**

GYNECARE INTERGEL Solution is a sterile, nonpyrogenic, amber colored,
viscous solution of sodium hyaluronate, which has been ionically
crosslinked with ferric ions and provides a transient viscous,
lubricious coating on the peritoneal surfaces following surgical
procedures*.*

GYNECARE INTERGEL Solution is packaged in a 300 mL low density
polyethylene bellows-type bottle, which is provided sterile in a plastic
tray using a Tyvek^^ lid. When stored at refrigerated (2-8 °C) or
controlled room temperature (15 - 30°C), INTERGEL has a stable shelf
life of 24 months.

### IV. CONTRAINDICATIONS 

GYNECARE INTERGEL Solution is contraindicated in patients with pelvic or
abdominal infection.

**V. WARNINGS AND PRECAUTIONS**

The warnings and precautions can be found in the GYNECARE INTERGEL
Solution labeling, which is available on the FDA web site at
*http://www.fda.gov/cdrh/pdf/p990015.pdf.*

## **VI. ALTERNATIVE PRACTICES AND PROCEDURES**

Practices intended to minimize adhesion formation include good surgical
technique with attention to gentle and minimal tissue handling,
meticulous hemostasis and avoidance of foreign particles, e.g., talc,
lint, and use of adjuvants such as crystalloid solutions. Alternative
devices approved as adjuncts intended to reduce adhesions include
INTERCEED (TC7) Absorbable Adhesion Barrier (Ethicon, Inc.) and
SEPRAFILM Bioresorbable Membrane (Genzyme Corp.)

**VII. ADVERSE EFFECTS**

Table 1 reports the local (surgical site) adverse events observed in
patients treated with INTERGEL Solution during an international,
randomized, double-masked, multi-center study comparing the safety and
effectiveness of GYNECARE INTERGEL Solution (300 mL) and lactated
Ringer's solution (300 mL) in 281 patients (GYNECARE INTERGEL Solution:
143 patients; lactated Ringer's solution: 138 patients).

**Table 1: Local (Surgical Site) Adverse Events**

+--------------------------+----------+---------+-----------+---------+
|                          | Intergel |         | Control   |         |
+--------------------------+----------+---------+-----------+---------+
| \# Patients Enrolled     | 143      |         | 138       |         |
+--------------------------+----------+---------+-----------+---------+
| Incision inflammation    | 8        | (5.6%)  | 8         | (5.8%)  |
+--------------------------+----------+---------+-----------+---------+
| Incision opening         | 7        | (4.9%)  | 5         | (3.6%)  |
+--------------------------+----------+---------+-----------+---------+
| Pain:                    | 9        | (6.3%)  | 13        | (9.4%)  |
|                          |          |         |           |         |
| > Incisional             | 39       | (27.3%) | 42        | (30.4%) |
| >                        |          |         |           |         |
| > Abdominal              | 3        | (2.1%)  | 3         | (2.2%)  |
| >                        |          |         |           |         |
| > Pelvic                 | 13       | (9.1%)  | 7         | (5.1%)  |
| >                        |          |         |           |         |
| > Back                   |          |         |           |         |
+--------------------------+----------+---------+-----------+---------+
| Infection:               | 8^a^     | (5.6%)  | 4^b^      | (2.9%)  |
|                          |          |         |           |         |
| Possibly device related  | 3^c^     | (2.1%)  | 1^d^      | (0.7%)  |
| (Investigator            |          |         |           |         |
| assessment)              |          |         |           |         |
+--------------------------+----------+---------+-----------+---------+

^a^ bladder; wound(2); pelvic/wound; unspecified(2); chlamydia; vaginal

^b^ wound(2); unspecified; vaginal

^c^ bladder; pelvic/wound; unspecified

^d^ wound

Table 2 reports systemic adverse events observed in 5% or more of the
study patients.

**Table 2: Systemic Adverse Events Reported Greater than 5%,**

**Number (%) of Patients**

+------------------------------+---+----------+---+------+---+-----------+---+-------+
| Body System                  | I |          |   |      | l |           |   |       |
|                              | N |          |   |      | a |           |   |       |
| Preferred Term               | T |          |   |      | c |           |   |       |
|                              | E |          |   |      | t |           |   |       |
|                              | R |          |   |      | a |           |   |       |
|                              | G |          |   |      | t |           |   |       |
|                              | E |          |   |      | e |           |   |       |
|                              | L |          |   |      | d |           |   |       |
|                              |   |          |   |      | R |           |   |       |
|                              | ( |          |   |      | i |           |   |       |
|                              | N |          |   |      | n |           |   |       |
|                              | = |          |   |      | g |           |   |       |
|                              | 1 |          |   |      | e |           |   |       |
|                              | 4 |          |   |      | r |           |   |       |
|                              | 3 |          |   |      | ' |           |   |       |
|                              | ) |          |   |      | s |           |   |       |
|                              |   |          |   |      | S |           |   |       |
|                              |   |          |   |      | o |           |   |       |
|                              |   |          |   |      | l |           |   |       |
|                              |   |          |   |      | u |           |   |       |
|                              |   |          |   |      | t |           |   |       |
|                              |   |          |   |      | i |           |   |       |
|                              |   |          |   |      | o |           |   |       |
|                              |   |          |   |      | n |           |   |       |
|                              |   |          |   |      | ( |           |   |       |
|                              |   |          |   |      | N |           |   |       |
|                              |   |          |   |      | = |           |   |       |
|                              |   |          |   |      | 1 |           |   |       |
|                              |   |          |   |      | 3 |           |   |       |
|                              |   |          |   |      | 8 |           |   |       |
|                              |   |          |   |      | ) |           |   |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Body as a Whole**          | * |          | * |      | * |           | * |       |
|                              | * |          | * |      | * |           | * |       |
| Pain                         | 1 |          | ( |      | 1 |           | ( |       |
|                              | 4 |          | 1 |      | 3 |           | 9 |       |
| Headache                     | 3 |          | 0 |      | 7 |           | 9 |       |
|                              | * |          | 0 |      | * |           | . |       |
| Fever                        | * |          | ) |      | * |           | 3 |       |
|                              |   |          | * |      |   |           | ) |       |
| Allergic reaction            | 1 |          | * |      | 1 |           | * |       |
|                              | 2 |          |   |      | 1 |           | * |       |
|                              | 2 |          | ( |      | 1 |           |   |       |
|                              |   |          | 8 |      |   |           | ( |       |
|                              | 4 |          | 5 |      | 3 |           | 8 |       |
|                              | 5 |          | . |      | 7 |           | 0 |       |
|                              |   |          | 3 |      |   |           | . |       |
|                              | 2 |          | ) |      | 1 |           | 4 |       |
|                              | 5 |          |   |      | 9 |           | ) |       |
|                              |   |          | ( |      |   |           |   |       |
|                              | 3 |          | 3 |      | 1 |           | ( |       |
|                              |   |          | 1 |      | 0 |           | 2 |       |
|                              |   |          | . |      |   |           | 6 |       |
|                              |   |          | 5 |      |   |           | . |       |
|                              |   |          | ) |      |   |           | 8 |       |
|                              |   |          |   |      |   |           | ) |       |
|                              |   |          | ( |      |   |           |   |       |
|                              |   |          | 1 |      |   |           | ( |       |
|                              |   |          | 7 |      |   |           | 1 |       |
|                              |   |          | . |      |   |           | 3 |       |
|                              |   |          | 5 |      |   |           | . |       |
|                              |   |          | ) |      |   |           | 8 |       |
|                              |   |          |   |      |   |           | ) |       |
|                              |   |          | ( |      |   |           |   |       |
|                              |   |          | 2 |      |   |           | ( |       |
|                              |   |          | . |      |   |           | 7 |       |
|                              |   |          | 1 |      |   |           | . |       |
|                              |   |          | ) |      |   |           | 2 |       |
|                              |   |          | \ |      |   |           | ) |       |
|                              |   |          | * |      |   |           |   |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Digestive**                | * |          | * |      | * |           | * |       |
|                              | * |          | * |      | * |           | * |       |
| Nausea                       | 1 |          | ( |      | 1 |           | ( |       |
|                              | 0 |          | 7 |      | 0 |           | 7 |       |
| Constipation                 | 6 |          | 4 |      | 0 |           | 2 |       |
|                              | * |          | . |      | * |           | . |       |
| Flatulence                   | * |          | 1 |      | * |           | 5 |       |
|                              |   |          | ) |      |   |           | ) |       |
| Vomiting                     | 6 |          | * |      | 6 |           | * |       |
|                              | 6 |          | * |      | 5 |           | * |       |
| Dyspepsia                    |   |          |   |      |   |           |   |       |
|                              | 4 |          | ( |      | 5 |           | ( |       |
|                              | 7 |          | 4 |      | 6 |           | 4 |       |
|                              |   |          | 2 |      |   |           | 7 |       |
|                              | 3 |          | . |      | 3 |           | . |       |
|                              | 5 |          | 6 |      | 5 |           | 1 |       |
|                              |   |          | ) |      |   |           | ) |       |
|                              | 1 |          |   |      | 1 |           |   |       |
|                              | 3 |          | ( |      | 4 |           | ( |       |
|                              |   |          | 3 |      |   |           | 4 |       |
|                              | 1 |          | 2 |      | 1 |           | 0 |       |
|                              | 4 |          | . |      | 0 |           | . |       |
|                              |   |          | 9 |      |   |           | 6 |       |
|                              |   |          | ) |      |   |           | ) |       |
|                              |   |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 2 |      |   |           | 2 |       |
|                              |   |          | 4 |      |   |           | 5 |       |
|                              |   |          | . |      |   |           | . |       |
|                              |   |          | 5 |      |   |           | 4 |       |
|                              |   |          | ) |      |   |           | ) |       |
|                              |   |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 9 |      |   |           | 1 |       |
|                              |   |          | . |      |   |           | 0 |       |
|                              |   |          | 1 |      |   |           | . |       |
|                              |   |          | ) |      |   |           | 1 |       |
|                              |   |          |   |      |   |           | ) |       |
|                              |   |          | ( |      |   |           |   |       |
|                              |   |          | 9 |      |   |           | ( |       |
|                              |   |          | . |      |   |           | 7 |       |
|                              |   |          | 8 |      |   |           | . |       |
|                              |   |          | ) |      |   |           | 2 |       |
|                              |   |          |   |      |   |           | ) |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Urogenital**               | * |          | * |      | * |           | * |       |
|                              | * |          | * |      | * |           | * |       |
| Dysmenorrhea                 | 4 |          | ( |      | 4 |           | ( |       |
|                              | 4 |          | 3 |      | 0 |           | 2 |       |
|                              | * |          | 0 |      | * |           | 9 |       |
|                              | * |          | . |      | * |           | . |       |
|                              |   |          | 8 |      |   |           | 0 |       |
|                              | 2 |          | ) |      | 2 |           | ) |       |
|                              | 5 |          | * |      | 2 |           | * |       |
|                              |   |          | * |      |   |           | * |       |
|                              |   |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 1 |      |   |           | 1 |       |
|                              |   |          | 7 |      |   |           | 5 |       |
|                              |   |          | . |      |   |           | . |       |
|                              |   |          | 5 |      |   |           | 9 |       |
|                              |   |          | ) |      |   |           | ) |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Nervous**                  | * |          | * |      | * |           | * |       |
|                              | * |          | * |      | * |           | * |       |
| Insomnia                     | 3 |          | ( |      | 4 |           | ( |       |
|                              | 7 |          | 2 |      | 0 |           | 2 |       |
| Dizziness                    | * |          | 5 |      | * |           | 9 |       |
|                              | * |          | . |      | * |           | . |       |
|                              |   |          | 9 |      |   |           | 0 |       |
|                              | 2 |          | ) |      | 2 |           | ) |       |
|                              | 0 |          | * |      | 2 |           | * |       |
|                              |   |          | * |      |   |           | * |       |
|                              | 1 |          |   |      | 1 |           |   |       |
|                              | 5 |          | ( |      | 3 |           | ( |       |
|                              |   |          | 1 |      |   |           | 1 |       |
|                              |   |          | 4 |      |   |           | 5 |       |
|                              |   |          | . |      |   |           | . |       |
|                              |   |          | 0 |      |   |           | 9 |       |
|                              |   |          | ) |      |   |           | ) |       |
|                              |   |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 1 |      |   |           | 9 |       |
|                              |   |          | 0 |      |   |           | . |       |
|                              |   |          | . |      |   |           | 4 |       |
|                              |   |          | 5 |      |   |           | ) |       |
|                              |   |          | ) |      |   |           |   |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Respiratory**              | * |          | * |      | * |           | * |       |
|                              | * |          | * |      | * |           | * |       |
| Cough, increased             | 3 |          | ( |      | 2 |           | ( |       |
|                              | 0 |          | 2 |      | 6 |           | 1 |       |
| Rhinitis                     | * |          | 1 |      | * |           | 8 |       |
|                              | * |          | . |      | * |           | . |       |
|                              |   |          | 0 |      |   |           | 8 |       |
|                              | 1 |          | ) |      | 8 |           | ) |       |
|                              | 1 |          | * |      |   |           | * |       |
|                              |   |          | * |      | 7 |           | * |       |
|                              | 8 |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 7 |      |   |           | 5 |       |
|                              |   |          | . |      |   |           | . |       |
|                              |   |          | 7 |      |   |           | 8 |       |
|                              |   |          | ) |      |   |           | ) |       |
|                              |   |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 5 |      |   |           | 5 |       |
|                              |   |          | . |      |   |           | . |       |
|                              |   |          | 6 |      |   |           | 1 |       |
|                              |   |          | ) |      |   |           | ) |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Cardiovascular**           | * |          | * |      | * |           | * |       |
|                              | * |          | * |      | * |           | * |       |
| Tachycardia                  | 1 |          | ( |      | 1 |           | ( |       |
|                              | 5 |          | 1 |      | 5 |           | 1 |       |
|                              | * |          | 0 |      | * |           | 0 |       |
|                              | * |          | . |      | * |           | . |       |
|                              |   |          | 5 |      |   |           | 9 |       |
|                              | 4 |          | ) |      | 7 |           | ) |       |
|                              |   |          | * |      |   |           | * |       |
|                              |   |          | * |      |   |           | * |       |
|                              |   |          |   |      |   |           |   |       |
|                              |   |          | ( |      |   |           | ( |       |
|                              |   |          | 2 |      |   |           | 5 |       |
|                              |   |          | . |      |   |           | . |       |
|                              |   |          | 8 |      |   |           | 1 |       |
|                              |   |          | ) |      |   |           | ) |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Hemic and Lymphatic**      |   | **19**   |   | **   |   | **16**    |   | **(11 |
|                              |   |          |   | (13. |   |           |   | .6)** |
| Anemia                       |   | 12       |   | 3)** |   | 13        |   |       |
|                              |   |          |   |      |   |           |   | (9.4) |
|                              |   |          |   | (    |   |           |   |       |
|                              |   |          |   | 8.4) |   |           |   |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+
| **Skin**                     |   | **13**   |   | *    |   | **13**    |   | **(9  |
|                              |   |          |   | *(9. |   |           |   | .4)** |
| Pruritus                     |   | 8        |   | 1)** |   | 10        |   |       |
|                              |   |          |   |      |   |           |   | (7.2) |
|                              |   |          |   | (    |   |           |   |       |
|                              |   |          |   | 5.6) |   |           |   |       |
+------------------------------+---+----------+---+------+---+-----------+---+-------+

\*p = 0.048, Fisher\'s Exact test.

In one randomized non-blinded laparoscopy trial of patients in the
United States (221 subjects), wound infections were reported for 5
GYNECARE INTERGEL Solution patients (4.4%) and no patients (0.0%) in the
control group (lactated Ringer's solution). There was one report of a
possible, post-operative pelvic infection in the control group (1.0%).
In a similar randomized non-blinded laparoscopy trial in Europe (144
patients), there were 5 reports of possible, post-operative pelvic
infection (6.8%) in the GYNECARE INTERGEL Solution patients, and one
report(1.4%) in the control group.

**VIII. MARKETING HISTORY**

GYNECARE INTERGEL Solution has been marketed in Europe, Canada, the
Middle East and South Africa since 1998.

GYNECARE INTERGEL Solution has not been withdrawn from the market for
any reason related to the safety or effectiveness of the product.

**IX. SUMMARY OF PRECLINICAL STUDIES**

**Biocompatibility and Toxicology Studies:**\
Safety studies conducted in support of the safety of GYNECARE INTERGEL
Adhesion Prevention Solution included both standard biocompatibility
studies and product specific toxicology studies.

### Biocompatibility Studies:

The biocompatibility studies performed in support of the safety of
GYNECARE INTERGEL Solution were *In Vitro* Cytotoxicity, Dermal
Sensitization, Pyrogenicity and Hemolysis. No cytotoxicity, dermal
sensitization, pyrogenicity nor hemolysis were detected in any of these
studies. These studies demonstrated that GYNECARE INTERGEL Solution is
not cytotoxic, not a dermal sensitizer, not pyrogenic and not hemolytic
under the conditions of the studies performed.

### *In Vivo* Acute Toxicity:

Seven acute toxicity studies were conducted with GYNECARE INTERGEL
Solution administered intraperitoneally (i.p.) using Swiss-Webster mice,
Fischer rats, New Zealand White rabbits, and Beagle dogs. In the acute
toxicity studies, GYNECARE INTERGEL did not produce significant
treatment-related clinical signs of toxicity, effects on body weight or
weight gain, or gross lesions following intraperitoneal administration
at dose volumes up to 20 mL/kg in sexually immature Fischer 344 rats, 50
mL/kg in Beagle dogs, 100 mL/kg in Swiss-Webster mice and sexually
mature Fischer 344 rats, and 150 mL/kg in New Zealand White rabbits.

One Beagle dog exhibited transient, systemic toxicity following i.p.
administration of 100 mL/kg GYNECARE INTERGEL Solution and clinical
signs of toxicity and mortality were observed at dose volume of 150
mL/kg in Swiss-Webster mice and sexually immature Fischer 344 rats.
Transient reduction in food consumption and fecal output, effects on
body weights and weight gains, changes in various clinical pathology
parameters (only at the high dose), and granulomatous peritonitis were
also observed in sexually immature Fischer 344 rats following i.p.
administration at dose volumes from 30 to 100 mL/kg GYNECARE INTERGEL
Solution. The adverse systemic toxicity in the sexually immature Fischer
344 rats appears to be idiosyncratic, especially since older rats of the
same strain and in one study, the same batch, did not experience the
same toxicity or constellation of gross lesions associated with the
peritonitis.

The highest dose of GYNECARE INTERGEL Solution that did not cause any
toxicity was 25 ml/kg (in sexually immature Fischer 344 rats). This dose
is 5 times higher than the recommended clinical instillate of 5 ml/kg.

### Multiple-Dose Sub-Chronic Toxicity:

The toxicity of GYNECARE INTERGEL Solution following repeated dose
administration was evaluated using Beagle dogs. In the multiple dose
toxicity studies, no mortality occurred in animals injected i.p. with
GYNECARE INTERGEL Solution at dose volumes up to 15 mL/kg/dose every
third day for 28 days. There were no treatment-related differences in
clinical pathology (i.e. hematology, coagulation, blood chemistry and
urinalysis) or in organ weights. The only treatment-related changes
apparent upon gross or microscopic examination consisted of an
accumulation of an iron-containing residue of the formulation in the
lymph nodes draining the abdominal cavity, in mesothelial cells covering
the abdominal viscera and/or in macrophages in the omentum or on the
serosal surface of the abdominal and pelvic viscera. No evidence of
systemic toxicity was observed in dogs from repeated intraperitoneal
injection of GYNECARE INTERGEL Solution at dosage levels of 5, 10 and 15
mL/kg/dose.

### Reproductive Toxicity:

The potential toxic effects of GYNECARE INTERGEL Solution on
reproductive capabilities were evaluated using female Sprague-Dawley
rats. The studies were designed to evaluate F0 estrous cycles, mating,
conception, parturition, lactation and weaning, as well as F1 survival,
growth and development.

In the fertility and general reproductive toxicity study of GYNECARE
INTERGEL Solution in rats, dose volumes of 5, 15, and 25 mL/kg given
i.p. every third day beginning 19 days prior to cohabitation until
gestation day 6 produced no treatment-related effects on fertility or
reproductive parameters, except for slight to significant reductions in
the mean number of implantation sites and viable fetuses depending upon
the volume of GYNECARE INTERGEL Solution administered. In a subsequent
study, this effect was significantly reduced when dosing with GYNECARE
INTERGEL Solution (25 mL/kg/dose) was stopped one day prior to
cohabitation and eliminated when dosing was stopped seven days prior to
cohabitation.

### Conclusions of Toxicity and Biocompatibility Testing:

The toxicity and biocompatibility studies conducted with GYNECARE
INTERGEL Solution demonstrated that this device is non-cytotoxic,
non-toxic in mice, rats, rabbits, and dogs *in vivo* acutely and
sub-chronically, non-hemolytic in rabbit blood, non-pyrogenic in
rabbits, non-sensitizing in guinea pigs and non-toxic to fertility and
reproductive parameters when the dosing interval was considered.

#### Preclinical Effectiveness Studies:

#### Numerous studies were performed to determine the formulation of GYNECARE INTERGEL Solution, using primarily the rabbit uterine horn simple abrasion model and the rabbit cecal/large bowel/sidewall abrasion model. When instilled prior to closing the abdomen, GYNECARE INTERGEL Solution was found to reduce adhesion formation in both of these model systems. (p\<0.05). 

GYNECARE INTERGEL Solution was tested against a low viscosity hyaluronic
acid (HA) formulation in the rabbit cecal/large bowel/sidewall abrasion
model. Animals received 15 mL of GYNECARE INTERGEL Solution or HA; those
in the surgical group did not receive any treatment. Adhesions were
evaluated seven (±1) days later. Adhesions to the sidewall were
prevented in all animals treated with GYNECARE INTERGEL Solution (N=6);
whereas in animals treated with HA, 40% of the sidewall was involved in
adhesions compared with 66% in control animals. The number of sidewalls
with no adhesions was also evaluated. GYNECARE INTERGEL Solution
completely prevented adhesions to all sidewalls (6 of 6 animals),
whereas HA completely prevented adhesions to the sidewall in 2 of 7
animals, compared to 0 of 7 control animals.

#### Effects on Wound Healing:

#### The effects of GYNECARE INTERGEL Solution on colonic anastomosis and incision line wound healing were evaluated in female Long-Evans rats. In this study, the ascending colon was transected at a point approximately 2.5 cm aboral to the ileocecal junction and the transected ends were anastomosed with plain gut suture. Either 15 mL/kg saline, 5 mL/kg or 15 ml/kg GYNECARE INTERGEL Solution were applied to the colonic anastomosis and adjacent peritoneum. A fourth group of animals served as the sham controls and did not receive any treatment except for surgery. The final analysis of the study results demonstrated that intraperitoneal administration of GYNECARE INTERGEL Solution at dose volumes up to 15 mL/kg following surgery did not adversely affect healing of colonic anastomoses or incisional wounds in rats.

**Effects on Infection Potentiation**

The ability of GYNECARE INTERGEL Solution to potentiate infections
caused by implantation of fecal material into the abdomen was evaluated
in female Sprague-Dawley rats. Animals were divided, 20 per group, among
the surgical control group, Ringer's Lactate High Dose (15 ml/kg) or Low
Dose (5 ml/kg), and GYNECARE INTERGEL Solution High Dose (15 ml/kg) or
Low Dose (5 ml/kg). The mortality rate was5/20 for the control animals,
3/20 for the Ringer's Lactate Low Dose and 5/20 for the High Dose and
the mortality rate was 5/20 for the GYNECARE INTERGEL Low Dose and 9/20
for the High Dose. No significant differences in abscess scores for the
liver, bowel, omentum, or \"Other\" sites were observed between any of
the treatment groups. In contrast, treatment with GYNECARE INTERGEL
Solution produced decreases in abscesses in the abdominal wall and in
total abscess formation relative to the surgical control group. The low
dose GYNECARE INTERGEL Solution group also had a lower total abscess
score than the low dose Ringer\'s Lactate control group. The results of
this study demonstrate that intraperitoneal administration of GYNECARE
INTERGEL Solution at dose volumes up to 15 mL/kg results in increased
deaths attributed to infection than similar doses of Ringer's lactate,
but also results in lower abscess score than similar doses of Ringer's
lactate.

This study was repeated using a model of mixed bacterial flora with a
larger group of animals, powered to detect a difference between LD~50~
and LD~75~ at the clinical dose of 5ml/kg. In this study, no difference
on mortality or abscess formation was observed in animals treated with
lactated Ringer's solution compared with GYNECARE INTERGEL Solution.

### Absorption, Distribution, and Excretion Studies

Several exploratory absorption, distribution, and excretion studies were
conducted in rats, dogs and monkeys in which serum levels of HA and iron
were determined following i.p. administration of GYNECARE INTERGEL
Solution. These studies demonstrated that slight increases in serum iron
were observed within the first 24 to 48 hours following dose
administration. Serum HA concentrations were shown to increase relative
to GYNECARE INTERGEL Solution administered intraperitoneally The
elevated serum HA levels are transient and do not suggest accumulation
at the clinical intended dose (5 mL/kg), or at doses up to 30 mL/kg.
Serum HA concentrations consistently returned to near pre-dose HA levels
within 7 days or earlier, depending on the does; the greater the dose,
the longer the time required to return to pre-dose levels

Information from autoradiography study in rats demonstrated that the
pattern, mechanism, and extent of absorption, distribution, metabolism,
and elimination of exogenous HA from the i.p. administered ferric
hyaluronate (FeHA) solution appears to be the same as exogenous HA
administered as HA alone. The tissues responsible for endogenous HA
clearance also appear to efficiently metabolize the exogenous HA. The
only difference between the two formulations appears to be a slightly
longer residence time at the site following i.p. administration of FeHA.
The delay in absorption of FeHA relative to HA, from the peritoneal
cavity is most probably due to the greater viscosity of the ionically
crosslinked formulation. From these studies, it is estimated that
GYNECARE INTERGEL Solution clearance from the peritoneum is
approximately twice that of HA. The elimination half-life (T~1/2~) of
GYNECARE INTERGEL Solution in humans is expected to be approximately 51
hours.

### Effectiveness of FeHA in Other Animal Models

Preclinical evaluations were conducted in three studies with a rat
cecal/liver adhesion model, In each study abrasions were made by wiping
the cecum with gauze until punctate bleeding developed. Three 8-mm
lesions were created on each side of the abdominal wall by removing a
layer of the peritoneum and transverse abdominal muscle with a stainless
steel biopsy punch. All accessible surfaces of the liver were abraded by
rubbing them with the wooden end of a sterile swab. The injured sites
received one of various test solutions. Animals in the surgical control
group did not receive any treatment. The sites were examined for the
extent of adhesions 7 days later. In all cases, the GYNECARE INTERGEL
Solution-treated groups had significantly (p\<0.05) reduced adhesions to
the cecum and the liver lobes compared with the control group.

#### Stability Studies: 

Stability studies were completed to support the shelf life of the
product using the bellow packaging configuration. The results of the
testing demonstrated that GYNECARE INTERGEL Solution has a shelf-life of
24 months when stored at 15 - 30° or 2-8°C.

X.  **SUMMARY OF CLINICAL EVALUATIONS**

GYNECARE INTERGEL Solution has been studied in a pilot study and pivotal
study in female patients undergoing peritoneal cavity surgery by
laparotomy with a planned second-look laparoscopy. The purpose of these
studies was to evaluate the safety and effectiveness of the device in
reducing post-surgical adhesions. Patients were administered 300 mL of
GYNECARE INTERGEL Solution or lactated Ringer\'s Solution as an
intraperitoneal instillate at the completion of the laparotomy
procedure. Adhesions were assessed at prospectively determined anatomic
sites, using prospective scales for extent and severity, before and
after adhesiolysis at baseline laparotomy, and at second look
laparoscopy. Safety was assessed based on adverse events recorded
throughout the study, on clinical laboratory tests performed at baseline
and post-therapy, and on gross evaluation at second-look.

PILOT STUDY

The pilot study was a randomized, unmasked, single investigator / single
center trial of 23 patients to evaluate the preliminary safety and use
of 300cc INTERGEL Solution compared to 300cc lactated Ringers control in
female patients undergoing laparotomy for infertility. The pilot study
enrolled 23 women, aged eighteen to forty-five year, undergoing limited,
class 1 (clean), open peritoneal cavity surgery. The most common
procedures were adhesiolysis and myomectomy performed for infertility. A
total of 21 patients, 11 treatment and 10 control, completed the second
look laparoscopy at 4 to 12 weeks after the initial surgery as part of
the treatment plan. Eighteen pre-specified anatomic sites (Table 2) for
adhesion incidence, extent and severity, as well as any other
co-incident effects were evaluated during the second look laparoscopy.
The mean incidence of baseline adhesions was 3.55 [+]{.underline} 4.52
for the 11 INTERGEL Solution patients and 4.33 [+]{.underline} 3.93 for
the 9 control patients. (One control patient who had 17 adhesions at
baseline, all of which reformed, was excluded from the analysis). At
second look laparoscopy, the mean incidence of sites with adhesions was
6.09 [+]{.underline} 4.59 for the INTERGEL Solution patients and 11.00
[+]{.underline} 3.24 for the control patients (p=0.015). The safety
profile was comparable for the 2 groups.

PIVOTAL STUDY

STUDY DESIGN

The pivotal study was designed to be a randomized, 12 center, 200
patient study to evaluate the safety and effectiveness of applying 300cc
of Intergel compared to 300cc of Lactated Ringers at the end of clean
(no gastro-intestinal or genito-urinary tract breach; no infectious
process), peritoneal cavity laparotomy procedures.

The main criteria for inclusion in the study were:

-   female patients 18 to 45 years of age requiring peritoneal cavity
    surgery via laparotomy with preservation of fertility

-   patients scheduled for Day 7-28 post-surgical laboratory
    determinations

-   patients who will be scheduled for a second-look laparoscopy as part
    of their treatment plan targeted for 6 to 12 weeks after the initial
    surgical procedure

The main preoperative criteria for exclusion in the study were:

-   pregnant or lactating patients

-   patients undergoing tubal sterilization, reversal of sterilization,
    or tubal implantation

-   patients currently receiving cancer therapy including drugs and
    radiation

-   patients who have lymphatic, hematologic or coagulation disorders,
    or patients taking coagulants

-   patients with a history of hemochromatosis

-   patients with hepatic or renal disorders

-   patients who are taking oral or parenteral hypoglycemic agents for
    diabetes

-   patients whose preoperative laboratory values are outside 20% of the
    normal range and are considered clinically significant

-   patients who are immunocompromised or have autoimmune disorders

-   patients who are unable to process large fluid loads, such as
    patients with congestive heart failure

The main intraoperative criteria for exclusion in the study were:

-   patients with 12 or more of the 24 anatomical sites involved with
    adhesions

-   patients receiving any peritoneal instillate containing
    corticosteroids, NSAIDs or Dextran

-   patients in whom any absorbable hemostat is left in the
    abdominal/peritoneal cavity

-   patients receiving any adhesion prevention adjuvant

-   patients who will need postoperative hydrotubation

-   patients presenting with pelvic or abdominal infection

-   patients who will undergo peritoneal grafting as part of their
    postoperative procedure

-   patients in who fibrin glue or other thrombogenic agents are used

-   any surgical procedure at the time of the initial laparotomy that
    involves opening the gastrointestinal or urinary tract

TREATMENT PROTOCOL

Enrolled patients were otherwise healthy eighteen to forty-five year old
women with limited adhesions (at less than twelve of twenty four sites),
desiring to retain fertility, having no sites excised during first
surgery and expecting to undergo second look laparoscopy as part of
their treatment plan at 6 to 12weeks. During second look laparoscopy,
twenty-four pre-specified anatomic sites (Table 3) were evaluated for
adhesion incidence, severity and extent, as well as any other
co-incident effects.

STUDY ENDPOINTS

The primary endpoint for effectiveness was Modified AFS score and the
secondary effectiveness endpoints were the proportion of sites with
adhesions, adhesion extent and adhesion severity. Safety was assessed
based on adverse events recorded throughout the study, on clinical
laboratory tests performed at baseline and post-therapy, and on gross
evaluation at second-look.

Twenty-four abdomino-pelvic sites were evaluated for incidence (yes /
no), severity (mild or severe) and extent of adhesions (\<1/3; 1/3 to
2/3; \>2/3). A composite score of 0 to 16 was determined per anatomic
site based on adhesion incidence, severity and extent at each site.
Scores per anatomic site (11 sites at first look; 24 sites at second
look) were to be combined to determine an adhesion final score per
patient.

##### Table 3: Anatomic Sites Evaluated

+-----------------------------------+-----------------------------------+
| Pilot Study                       | Pivotal Study                     |
+-----------------------------------+-----------------------------------+
| Anterior peritoneum,              | Caudal anterior peritoneum\*      |
|                                   |                                   |
| Small bowel,                      | Cephalad anterior peritoneum,     |
|                                   | right\*                           |
| Omentum                           |                                   |
|                                   | Cephalad anterior peritoneum,     |
| Large bowel                       | left\*                            |
|                                   |                                   |
| Anterior uterus,                  | Anterior peritoneum incision\*    |
|                                   |                                   |
| Posterior uterus,                 | Small bowel\*                     |
|                                   |                                   |
| Recto-sigmoid colon,              | Omentum\*                         |
|                                   |                                   |
| Posterior cul de sac,             | Large bowel, right\*              |
|                                   |                                   |
| Right pelvic side-wall,           | Large bowel, left\*               |
|                                   |                                   |
| Left pelvic side-wall,            | Anterior uterus,                  |
|                                   |                                   |
| Medial right ovary                | Posterior uterus,                 |
|                                   |                                   |
| Lateral right ovary               | Recto-sigmoid colon,              |
|                                   |                                   |
| Medial left ovary                 | Posterior cul de sac              |
|                                   |                                   |
| Lateral left ovary                | Right pelvic side-wall,           |
|                                   |                                   |
| Right ovarian fossa / posterior   | Left pelvic side-wall,            |
| broad ligament,                   |                                   |
|                                   | Medial right ovary                |
| Left ovarian fossa / posterior    |                                   |
| broad ligament,                   | Lateral right ovary               |
|                                   |                                   |
| Right tube and fimbria,           | Medial left ovary                 |
|                                   |                                   |
| Left tube and fimbria,            | Lateral left ovary                |
|                                   |                                   |
|                                   | Right ovarian fossa / posterior   |
|                                   | broad ligament,                   |
|                                   |                                   |
|                                   | Left ovarian fossa / posterior    |
|                                   | broad ligament,                   |
|                                   |                                   |
|                                   | Right tube                        |
|                                   |                                   |
|                                   | Right ampulla                     |
|                                   |                                   |
|                                   | Left tube                         |
|                                   |                                   |
|                                   | Left ampulla                      |
+-----------------------------------+-----------------------------------+

\*Extent of adhesion was assigned a moderate score if an adhesion was
present.

The American Fertility Society (AFS) scoring system is a method of
scoring adhesions at the tube and ovary described by The American
Fertility Society (Fertility and Sterility, vol. 49, No. 6, June 1988).
A score of 0 to 16 score is determined as per schema below (Table 4),
per tube and per ovary on each side: four scores are determined per
patient. The scores per anatomic side are added and the lower score per
side determines the final AFS score per patient. As each anatomic site,
tube / ovary, may score 0 to 16, and as the scores per side are added
and only the side with the lower score is reported, the possible AFS
score range is 0--32.

> **Table 4: American Fertility Score (AFS)**

  ----------------------------- --------------------- --------------------
  **AFS Score per site**        **Severity**          **Extent**

  0                             None                  none

  1                             Mild                  localized

  2                             Mild                  moderate

  4                             Mild                  extensive

  4                             Severe                localized

  8                             Severe                moderate

  16                            Severe                extensive
  ----------------------------- --------------------- --------------------

The INTERGEL pivotal clinical study adhesion score was determined by
applying the per site AFS score to each of twenty-four abdomino-pelvic
sites, adding the scores of all twenty four sites (no scores dropped)
and normalizing (dividing) by the number of sites.: the possible mAFS
score range per patient being 0--16. Extent of adhesion was planned to
be assigned a moderate score (1/3 to 2/3) for the anterior peritoneum,
small bowel, omentum and large bowel if an adhesion was present due to
anticipated difficulty in visualization and/or size. A total adhesion
score per patient was calculated, referred to as the modified AFS (mAFS)
score.

The standard AFS score was not a prospectively specified parameter of
adhesion evaluation and was not determined during clinical study
evaluations. However, an AFS score was calculated from mAFS score data
using three sites for each ovary and two sites for each tube; the higher
score of the right and left side was dropped; the lower score of the
right and left side per patient became the AFS score per patient.
Further analyses included shift tables in which the calculated AFS were
stratified into segments and the shift from baseline to second look was
tabulated. The strata included calculated AFS scores (range = 0 -- 32)
as indicated in Table 5:

**Table 5: Stratified AFS Scores**

  ------------------------------------------------- ---------------------
  **AFS Strata**                                    **Score**

  Minimal                                           0 -- 5

  Mild                                              6 -- 10

  Moderate                                          11 -- 20

  Severe                                            21 -32

  Minimal / mild                                    0 --10

  Moderate / severe                                 11 -- 32
  ------------------------------------------------- ---------------------

PATIENT ACCOUNTING AND DEMOGRAPHICS

The study was conducted at 11 US Centers and 5 European Centers. The
study enrolled 281 patients and 265 patients comprise the evaluable
patient population for which a second look effectiveness assessment was
performed. Therefore, 281 patients were available for safety data and
265 were evaluable for effectiveness. Table 6 provides the patient
accounting and demographics for the pivotal study:

##### Table 6: Pivotal Study Patient Accounting and Demographics

+--------------------------------------+-------+---+------+--------+------+
| ##                                   | **    |   |      | **Con  |      |
|                                      | Inter |   |      | trol** |      |
|                                      | gel** |   |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## \# treated                        | #     |   |      | ## 138 |      |
|                                      | # 143 |   |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## \# with no second-look            | ##    |   |      | ## 4   |      |
|                                      |  12\* |   |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## \# completed study                | #     |   |      | ## 134 |      |
|                                      | # 131 |   |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Demographics:                     | ##    | ( |      | 82     | (6   |
|                                      |       | 5 |      |        | 1.2) |
| ## Race, n (%)                       | 74    | 6 |      | 23     |      |
|                                      |       | . |      |        | (1   |
| > Caucasian                          | 28    | 5 |      | 4      | 7.2) |
| >                                    |       | ) |      |        |      |
| > Black                              | 4     |   |      | 22     | (    |
| >                                    |       | ( |      |        | 3.0) |
| > Oriental                           | 20    | 2 |      | 3      |      |
| >                                    |       | 1 |      |        | (1   |
| > Hispanic                           | 5     | . |      | 34.2   | 6.4) |
| >                                    |       | 4 |      |        |      |
| > Other                              | 33.8  | ) |      | 150.2  | (    |
|                                      |       |   |      |        | 2.2) |
| Age, mean, sd                        | 150.1 | ( |      |        |      |
|                                      |       | 3 |      |        | (    |
| Weight, mean, sd                     |       | . |      |        | 5.4) |
|                                      |       | 1 |      |        |      |
|                                      |       | ) |      |        | (3   |
|                                      |       |   |      |        | 1.8) |
|                                      |       | ( |      |        |      |
|                                      |       | 1 |      |        |      |
|                                      |       | 5 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 3 |      |        |      |
|                                      |       | ) |      |        |      |
|                                      |       |   |      |        |      |
|                                      |       | ( |      |        |      |
|                                      |       | 3 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 8 |      |        |      |
|                                      |       | ) |      |        |      |
|                                      |       |   |      |        |      |
|                                      |       | ( |      |        |      |
|                                      |       | 5 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 8 |      |        |      |
|                                      |       | ) |      |        |      |
|                                      |       |   |      |        |      |
|                                      |       | ( |      |        |      |
|                                      |       | 3 |      |        |      |
|                                      |       | 0 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 9 |      |        |      |
|                                      |       | ) |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Baseline Adhesion #, mean (0-24)  | ##    |   | ##   | #      | ##   |
|                                      |  3.65 |   |      | # 3.46 |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Baseline mAFS, mean (0-16)        | ##    |   | ##   | #      | ##   |
|                                      |  1.07 |   |      | # 1.07 |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Blood loss (cc), mean (sd)        | #     | # |      | ## 224 | ## ( |
|                                      | # 214 | # |      |        | 284) |
|                                      |       |   |      |        |      |
|                                      |       | ( |      |        |      |
|                                      |       | 2 |      |        |      |
|                                      |       | 1 |      |        |      |
|                                      |       | 4 |      |        |      |
|                                      |       | ) |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Operative Time (hrs), mean (sd)   | ##    | # |      | ##     | #    |
|                                      |  1.86 | # |      |  1.80  | # (0 |
|                                      |       |   |      |        | .85) |
|                                      |       | ( |      |        |      |
|                                      |       | 0 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 8 |      |        |      |
|                                      |       | 2 |      |        |      |
|                                      |       | ) |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Days to Discharge, mean (sd)      | #     | # |      | #      | ## ( |
|                                      | # 3.0 | # |      | # 3.0  | 1.7) |
|                                      |       |   |      |        |      |
|                                      |       | ( |      |        |      |
|                                      |       | 1 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 6 |      |        |      |
|                                      |       | ) |      |        |      |
+--------------------------------------+-------+---+------+--------+------+
| ## Days to second look, mean (sd)    | ##    | # |      | #      | #    |
|                                      |  60.4 | # |      | # 58.7 | # (2 |
|                                      |       |   |      |        | 1.4) |
|                                      |       | ( |      |        |      |
|                                      |       | 2 |      |        |      |
|                                      |       | 6 |      |        |      |
|                                      |       | . |      |        |      |
|                                      |       | 2 |      |        |      |
|                                      |       | ) |      |        |      |
+--------------------------------------+-------+---+------+--------+------+

\*1 patient was lost to follow-up

ANALYSIS AND RESULTS

The results for the primary effectiveness endpoint, mean mAFS, are
presented below in Table 7.

Table 7: Primary Effectiveness Results, Mean mAFS (Range 0-16)

  ------------------------- -------------- --------------- --------------
                            **Intergel**   **Control**     **p-value**

  N                         131            134             

  Baseline Score (Range     1.07           1.07            0.870
  0-16)                                                    

  2^nd^ Look Score (Range   1.36           2.32            0.002
  0-16)                                                    
  ------------------------- -------------- --------------- --------------

Baseline mean mAFS scores for the Intergel and Control Group were
statistically comparable (p=0.870), however, the second look mean mAFS
for Intergel was statistically significantly lower than the control
(p=0.002).

The secondary effectiveness outcomes are the mean incidence of adhesions
(range of 0-24), extent of adhesions (range of 0-3) and severity of
adhesions (range of 0-3). These baseline and second look laparoscopy
results are provided in Table 8 below.

**Table 8: Secondary Effectiveness Results**

+-------------------------+-------------+---------------+-------------+
|                         | *           | **Control**   | **p-value** |
|                         | *Intergel** |               |             |
+-------------------------+-------------+---------------+-------------+
| N                       | 131         | 134           |             |
+-------------------------+-------------+---------------+-------------+
| Baseline Incidence      | 3.65        | 3.46          | 0.744       |
| (Range 0-24)            |             |               |             |
+-------------------------+-------------+---------------+-------------+
| 2^nd^ Look Incidence    | 6.56        | 7.63          | 0.096       |
| (Range 0-24)            |             |               |             |
+-------------------------+-------------+---------------+-------------+
| Baseline Extent         | 0.29        | 0.30          | 0.964       |
|                         |             |               |             |
| (Range 0-3)             |             |               |             |
+-------------------------+-------------+---------------+-------------+
| 2^nd^ Look Extent       | 0.47        | 0.63          | 0.019       |
|                         |             |               |             |
| (Range 0-3)             |             |               |             |
+-------------------------+-------------+---------------+-------------+
| Baseline Severity       | 0.38        | 0.35          | 0.670       |
|                         |             |               |             |
| (Range 0-3)             |             |               |             |
+-------------------------+-------------+---------------+-------------+
| 2^nd^ Look Severity     | 0.52        | 0.73          | 0.007       |
|                         |             |               |             |
| (Range 0-3)             |             |               |             |
+-------------------------+-------------+---------------+-------------+

AFS SCORE

The effect that treatment had on the stratified AFS score is analyzed in
Table 9 below.

**Table 9: Shift Table of Baseline and 2^nd^ Look Stratified AFS Score**

  ------------------------ --------- -------------------- ------- ------- ------------- -------- ----- ------------- --------- --------- ------- ------------- ------------- -------- ------ ------------- --------- --------- -------------
                                     ***INTERGEL®                                                                                                ***Lactated                                                                   
                                     Solution***                                                                                                 Ringer\'s                                                                     
                                                                                                                                                 Solution***                                                                   

  *[AFS Category                                                                                                                                                                                                               
  Analysis]{.underline}*                                                                                                                                                                                                       

                                     *―――― Second Look                                                                                           *―――― Second                                                                  
                                     ――――*                                                                                                       Look ――――*                                                                    

                                     *Baseline*                           *Min.*        *Mild*                       *Mod.*    *Sev.*            *Baseline*    *Min.*        *Mild*          *Mod.*        *Sev.*              *p*

                                     *Total*                              *0-5*         *6-10*                       *11-20*   *21-32*           *Total*       *0-5*         *6-10*          *11-20*       *21-32*             

  *Minimal*                *0-5*     *109*                        *103*                 *4*                          *1*       *1*               *109*         *96*          *6*             *3*           *4*                 

  *Mild*                   *6-10*    *13*                         *10*                  *2*                          *1*       *0*               *8*           *4*           *1*             *2*           *1*                 

  *Moderate*               *11-20*   *7*                          *6*                   *1*                          *0*       *0*               *13*          *3*           *4*             *5*           *1*                 

  *Severe*                 *21-32*   *2*                          *2*                   *0*                          *0*       *0*               *4*           *2*           *1*             *0*           *1*                 

                                                                                                                                                                                                                               

  *Total Second-look*                *131*                        *121*                 *7*                          *2*       *1*               *134*         *105*         *12*            *10*          *7*                 

                                                                                                                                                                                                                               *0.001\**

                                                                                                                                                                                                                               *0.001\*\**

                                                                                                                                                                                                                               

  *[Binary                                                                                                                                                                                                                     
  Analysis]{.underline}*                                                                                                                                                                                                       

                                     *―――― Second Look                                                                                           *―――― Second                                                                  
                                     ――――*                                                                                                       Look ――――*                                                                    

                                     *Baseline*                           *Min./Mild*                  *Mod./Sev.*                               *Baseline*    *Min./Mild*                   *Mod./Sev.*                       *p*

                                     *Total*                              *0-10*                                     *11-32*                     *Total*       *0-10*                        *11-32*                           

  *Min./Mild*              *0-10*    *122*                *119*                                  *3*                                     *117*                 *107*                  *10*                                     

  *Mod./Sev.*              *11-32*   *9*                  *9*                                    *0*                                     *17*                  *10*                   *7*                                      

  *Total Second Look*                *131*                *128*                                  *3*                                     *134*                 *117*                  *17*                           *0.003*   

  *Relative Risk*                    *(INTERGEL®                                                                                                                                                                               
                                     Solution/Control):                                                                                                                                                                        
                                     0.195 95% CI: 0.065                                                                                                                                                                       
                                     to 0.583*                                                                                                                                                                                 
  ------------------------ --------- -------------------- ------- ------- ------------- -------- ----- ------------- --------- --------- ------- ------------- ------------- -------- ------ ------------- --------- --------- -------------

*\* p value determined using CMH test controlling for Baseline level
(ridit scores)*

*\*\*p value determined using CMH test controlling for Baseline level
(median scores)*

Analysis using the Cochran-Mantel-Haenszel test controlling for baseline
level indicates a statistically significant p value (p=0.001) between
treatment groups in the shift from one AFS adhesion category to another.
Combining the minimal and mild categories, and the moderate and severe
categories (binary analysis), at second-look there were 3 of 131
patients (2.3%) in the moderate/severe category compared to 17 of 134
control patients ( 12.7%; RR=0.195).

SAFETY

Sixteen (11.2%) patients treated with GYNECARE INTERGEL Solution and
seven patients (4.9%) treated with lactated Ringer's solution
experienced adverse events considered by the investigator to be
possibly, probably, or definitely related to treatment. These events
included abdominal and/or post-operative pain, fever, nausea, and
constipation, and all resolved spontaneously or with treatment.
Treatment-related serious adverse events were experienced by three
patients in the GYNECARE INTERGEL Solution group (two cases of abdominal
pain, one case of fever) and one patient in the lactated Ringer's
solution group (fever). Of the three patients treated with GYNECARE
INTERGEL Solution, one required rehospitalization and a diagnostic
laparoscopy. All three of these patients had a prolonged hospital stay
and received additional medications to resolve their symptoms. The
control group patient had a prolonged hospitalization and was treated
with medication to resolve her fever. There were no discontinuations due
to an adverse event and no deaths occurred during the study.

There were 10 Intergel patients and 4 control patients reported to have
infection in the study. Table 10 reports each of these patients and
reports the event and whether the investigator assessed the infection to
be related to the use of the device.

Table 10: Patients reported as having an infection

  ----------------------------------- -----------------------------------
  Adverse Event                       Related to device, Investigator

  Intergel Solution Treated Patients  
  (n=143)                             

  Chicken pox                         No

  Pelvis infection                    No

  Bladder pain, infection             Possibly

  Klebsiella wound infection,         Possibly
  abdominal pain                      

  Post-operative Infection            No

  Peritoneal fluid culture positive   No

  Wound abscess                       No

  Head cold                           No

  Vaginal fungal infection\*          No

  Infection\*                         Possibly

  Lactated Ringer's Solution Treated  
  Patients (n=138)                    

  Surgical site wound infection       Possibly

  Infection                           No

  Wound infection\*                   No

  Vaginal mycosis\*                   No
  ----------------------------------- -----------------------------------

\*European patient

The white blood cell analyses indicated a small, but statistically
significant increase in neutrophils on postoperative day 3 and day 7-28
and in lymphocytes on postoperative day 3, day 7-8, and at second look
laparoscopy for patients treated with GYNECARE INTERGEL Solution
compared to patients treated with lactated Ringer's solution.

**XI. PANEL RECOMMENDATIONS**

On January 12, 2000, the General and Plastic Surgery Devices Panel
recommended that this PMA was not approvable. The panel stated the data
did not provide a reasonable assurance the device was safe and
effective. The panel stated there were concerns regarding the safety of
GYNECARE INTERGEL Adhesion Prevention Solution in regards to the
potential contribution of the device to the infection rate. Also, the
panel stated the number, severity, and extent of adhesions was not
clinically different between the treatment and control patients.\
\
On June 2, 2000, the sponsor amended the PMA with a modified indications
for use for conservative gynecologic pelvic surgery. On November 15,
2000, the agency found the PMA not approvable because it did not provide
reasonable assurance that the product was safe and effective. On January
4, 2001, the sponsor requested that the PMA be reviewed by the Medical
Devices Dispute Resolution Panel. On September 6, 2001, the Medical
Device Dispute Resolution Panel reviewed the information in the PMA.

The issue discussed most by the Medical Device Dispute Resolution Panel
was whether the benefit shown for Intergel was clinically important. In
questioning both parties, the Panel was particularly interested in how
treatment affected the proportion of patients with moderate/severe
adnexal adhesions at second look. The Panel understood that the
percentage of individuals with moderate/severe AFS scores at second look
had uncertain value in predicting "hard" outcomes of interest (pain,
fertility, bowel obstruction). Nevertheless, they understood that the
AFS score probably was the best measure, given the constraints of what
is feasible, for a prospective clinical trial.

The Medical Device Dispute Resolution Panel had fewer questions about
the safety of Intergel and discounted the importance of the trend that
suggested a slightly higher infection risk for those receiving Intergel.

The Medical Device Dispute Resolution Panel recommended that this PMA be
approved without conditions. The Panel stated that Intergel showed a
statistically significant benefit over the lactated Ringer's solution
control, and that this evidence was sufficient for approval. Several
members did note that the benefit for Intergel was probably modest
clinically, but better than no therapy.

XIII. **CDRH DECISION**

Expedited processing was authorized on April 26, 1999, based on the
potential of GYNECARE INTERGEL to provide a specific public health
benefit by reducing the incidence, extent, and severity of newly formed
adhesions.\
\
Inspection of the Lifecore Biomedical, Inc. manufacturing facilities was
completed on December 28, 1999 and January 14, 2000 and was found to be
in compliance with the device Quality Systems Regulation.

CDRH carefully considered the discussions and recommendations of both
the General and Plastic Surgery Devices Panel and the Medical Device
Dispute Resolution Panels. CDRH concluded that the data gathered on the
use of the GYNECARE INTERGEL Solution are clinically meaningful and that
the data demonstrate that the benefits of the device outweigh the risks,
including the risk of infection. Therefore, the data contained in this
submission provide reasonable assurance of the safety and effectiveness
of GYNECARE INTERGEL Solution for its intended use as an intraperitoneal
instillate for reduction of adhesions following gynecological pelvic
surgery.

FDA issued an approval order on November 16, 2001.

**XIV. APPROVAL SPECIFICATIONS**

Directions for Use: See product labeling.

Hazard to Health from Use of the Device: See Indications,
Contraindications, Warnings, Precautions, and Adverse Reactions in the
labeling.

Postapproval Requirements and Restrictions: see the Approval Order.