**SUMMARY OF SAFETY AND EFFECTIVENESS DATA**

**I. GENERAL INFORMATION**

Device Generic Name: Topical Tissue Adhesive

Device Trade Name: Indermil™ Tissue Adhesive

Sponsor\'s Name and Address:

> United States Surgical, a division of Tyco Healthcare Group, LP.

150 Glover Ave.

Norwalk, CT 06856

Premarket Approval Application

(PMA) Number: P010002

Date of Panel Recommendation: None.

Date of GMP Inspection: November 7, 2001

Date of Notice of Approval

To the Applicant: May 22, 2002

**II.** **INDICATIONS FOR USE**

Indermil™ tissue adhesive is indicated for the closure of topical skin
incisions including laparoscopic incisions, and trauma-induced
lacerations in areas of low skin tension that are simple,
thoroughly-cleansed, and have easily approximated skin edges. Indermil
may be used in conjunction with, but not in place of, deep dermal
stitches.

**III. DEVICE DESCRIPTION**

Indermil™ is a sterile, liquid topical tissue adhesive composed of
*n*-Butyl-2-Cyanoacrylate monomer. Indermil™ tissue adhesive is supplied
in a 0.5g single patient use, plastic ampule. Each ampule is sealed
within a foil packet so the exterior of the ampule is also sterile.
Indermil™ remains liquid until exposed to water or water-containing
substances/ tissue, after which it cures (polymerizes) and forms a film
that bonds to the underlying surface.

**IV. CONTRAINDICATIONS**

Indermil™ tissue adhesive is not to be applied to subdermal layers of
tissue. The polymerized adhesive is not absorbed by tissues and may
elicit a foreign body reaction.

The tissue adhesive is not to be applied to any internal organs, blood
vessels, nerve tissue, mucosal surfaces or mucocutaneous junctions,
areas with dense natural hair, or within the conjunctival sac of the
eye.

The tissue adhesive is not to be applied to the surface of the eye. If
the eye is bonded closed, release eyelashes with warm water by covering
with a wet pad. The adhesive will bond to eye protein and will cause
periods of weeping which will help to release the adhesive. Keep the eye
covered until the adhesive is no longer adhered to the surface of the
eye -- usually within 1 to 3 days. Do not force the eye open.

The tissue adhesive is not to be applied to wounds subject to high skin
tension, or on areas of increased skin tension such as the elbows,
knees, or knuckles. The tissue adhesive is not to be used in areas of
skin excision.

The tissue adhesive is not to be applied to wounds that show evidence of
infection or gangrene.

The tissue adhesive is not to be used on patients with known
preoperative systemic infections, uncontrolled diabetes, or diseases or
conditions that are known to interfere with the wound healing process.

The tissue adhesive is not to be used on patients with a known
hypersensitivity to cyanoacrylate or formaldehyde.

**V. WARNINGS AND PRECAUTIONS**

Refer to device labeling for a list of the warnings and precautions.

**VI. ALTERNATE PRACTICES AND PROCEDURES**

Skin wounds can be closed utilizing various medical devices in order to
maintain tissue apposition during the critical phase of wound healing.
The most commonly utilized device is the non-absorbable monofilament
suture. The sutures remain in place for approximately 7-10 days, at
which time the patient returns to have the sutures removed. Similarly,
metal skin staples are utilized in the same fashion as sutures,
requiring a return visit for staple removal. Adhesive tapes have also
been used to hold skin wound edges together. In addition, another
commercially available tissue adhesive has been utilized to maintain
approximation of skin wound edges caused by surgical incisions or
traumatic lacerations.

**VIII. MARKETING HISTORY**

Indermil™ was first issued a Product License in the United Kingdom on
September 28, 1993. Indermil was granted the CE Mark in accordance with
the European Medical Device Directive (93/42/EEC) on December 12, 1995.
Since that time, Indermil™ has been sold throughout the European Union
and Switzerland, as well as the following international markets:
Australia, Canada, Colombia, Mexico, Hungary, Slovakia, Taiwan,
Thailand, India, Israel and Saudi Arabia.

Indermil™ has not been withdrawn from marketing for any reason relating
to the safety or effectiveness of the device.

**IX. SUMMARY OF PRECLINICAL STUDIES**

Preclinical studies were performed to evaluate the safety and
effectiveness of Indermil™ tissue adhesive in both the laboratory and in
animal models.

[Studies on the Safety of Indermil™: BiocompatIbility
Studies]{.underline}

Based on the categorization of medical devices by nature of body contact
and duration of contact described in the ISO 10993-1, Indermil^TM^ is
considered a *Surface-contacting device (ISO 10993-1, sect. 4.1.2)* with
a prolonged contact duration of *\> 24 hours to 30 days (ISO 10993-1,
sect. 4.2)*. Based on the information that is known about the safety of
butylcyanoacrylates, and the characteristics and intended use of
Indermil^TM^, the following biocompatibility tests were performed to
evaluate its safety:

-   Cytotoxicity

-   Sensitization

-   Irritation

-   Genotoxicity

The tests performed used an alternate formulation of Indermil^TM^,
referred to as LID-1187A that differed only slightly in the amount of
SO~2~ (sulfur dioxide) and stabilizer. Cytotoxicity, Sensitization, and
Irritation tests required by International Organization for
Standardization (ISO) 10993-1: Biological Evaluation of Medical Devices
-- Part 1: Evaluation and Testing (1997) were repeated for the
specification used during the Clinical Trials and maintained to the
present time. All testing was conducted in accordance with Good
Laboratory Practice Standards.

The test results demonstrate that Indermil^TM^ was found to be
non-cytotoxic to L929 cells when evaluated as a saline or MEM extract.
In addition, Indermil^TM^ did not cause delayed contact hypersensitivity
in the guinea pig, when assessed using the Guinea Pig Maximization test.
Indermil^TM^ was not considered to be an irritant to either intact or
abraded skin, when evaluated in rabbits. Lastly, Indermil™ was
considered to be non-mutagenic in strains of *Salmonella Typhimurium*
and non-clastogenic in cultured human lymphocytes. In conclusion,
biocompatibility testing demonstrates that Indermil^TM^ does not raise
any significant biocompatibility concerns.

####### [Studies on the Efficacy of Indermil™: In Vitro and In Vivo Testing]{.underline}

**In Vitro Studies Comparing Shear Strength and Fixture Times of
Adhesives**

To evaluate the efficacy of Indermil™ adhesive, batteries of studies
were performed first in the laboratory to evaluate the ability of the
adhesive to polymerize rapidly with adequate strength to perform as
indicated. Fixture time tests were performed with both 70% hospital
grade and 99.96% laboratory grade isopropyl alcohol. Inclusion of
samples cleaned with both 70% and 99.96% isopropyl alcohol was done to
assess the effect of surface water on fixture time and shear strength.

Performance studies on samples cleaned with 70% Isopropyl alcohol,
demonstrate that the Indermil^™^ tissue adhesive was equivalent, in
terms of fixture time, when compared to a legally-marketed medical
device. The legally-marketed device yielded higher shear strength than
Indermil™.

Performance studies were also done to evaluate the fixture times of
Indermil™ and a legally-marketed device on ABS fixtures pre-cleaned with
99.96% Isopropyl alcohol. The results show that the Indermil^™^ tissue
adhesive was faster in terms of fixture time when compared with the
other device. The Indermil^™^ tissue adhesive was slightly lower in
shear strength to the other device.

While there is no direct correlation between the in-vivo wound strength
and the in-vitro lap shear strength, these studies suggested that
Indermil^™^ tissue adhesive would provide the necessary strength during
wound healing to proceed to a clinical trial.

**In Vivo Wound Security and Wound Healing Strength of Indermil^™^
compared to an n-octylcyanoacrylate or wound closure tape:**

Full-thickness skin incisions were made on the backs of 84 rats and
closed with Indermil^™^, another legally-marketed device for tissue
closure, or wound closure tape. The rats were divided into three groups.
Each rat received two paravertebral incisions. Group One (N = 36)
received Indermil™ on one incision and the legally-marketed device on
the other incision. Group Two (N = 36) received Indermil™ on one
incision and Steri-Strips™ on the other incision. Group Three (N =12)
served as a control group and received Steri-Strips™ on both incisions.
Wound security and wound healing strengths were determined at closure
and again after 1 and 2 weeks. Initially all wound strength was provided
by the closure devices. After 1 week, strength was provided by wound
healing, and the closure devices provided no additional strength. At 2
weeks, healing was not inhibited and was similar in all groups. In
conclusion, Indermil^™^, the legally-marketed device, and wound closure
tape performed similarly by providing wound security for the first week
of healing and then not inhibiting the normal healing process.

**A Comparison of the Histological Effects of Indermil^™^ compared to an
n-octylcyanoacrylate or wound closure tape:**

A fourteen day study was conducted to compare skin wound healing between
three methods of incision closure (Indermil^™^, another legally-marketed
device for tissue closure, and wound closure tape). Two paravertebral
incisions were made into the skin of 18 rats and closed with either
Indermil^™^, the legally-marketed device, and wound closure tape which
resulted in 12 closures with each method. Four tissues closed by each
method were collected at 3, 7, and 14 days after closure. Histology
slides were prepared. Components of the tissue reaction to each closure
method were quantified which resulted in a histopathology rating for
each closure site.

The criteria for histopathology evaluation was based on eleven
histopathological variables. Each variable was rated on a scale from 0
to 3, where \"0\" was most favorable and \"3\" was least favorable.
Histopathology rating scores were based on the average of the
quantitative scores for each of the eleven variables. Evaluation of the
histopathology rating indicates that the wound closure tape had the
lowest rating at all timepoints, and thus, was the least reactive of the
3 closure methods. At 7 and 14 days, but not at 3 days, Indermil^™^ had
a lower rating than the legally-marketed device, suggesting less tissue
reactivity. However, the ratings for the legally-marketed device and
Indermil^™^ were essentially equal at 14 days, indicating that these two
products were comparable at that timepoint. Each closure device provided
no appreciable enhancement of the normal cellular response to healing.
At no time did any specimen demonstrate a histopathology rating greater
than 0.77 (where a score of 1.00 is defined as a mild reaction).
Therefore, all the specimens were determined to have elicited an
acceptable histological response. Indermil™ elicited a response similar
to the legally-marketed device and wound closure tape.

**X. [SUMMARY OF THE RESULTS OF THE CLINICAL INVESTIGATON]{.underline}**

A multi-center, prospective, randomized trial compared INDERMIL™ Tissue
Adhesive with traditional wound closure techniques to evaluate the
safety and efficacy of Indermil™. Patients were randomized to wound
closure using INDERMIL™ adhesive or to the comparator group where
alternative wound closure techniques (suture, staples, and adhesive
strips) were applied. A record was kept of the type, size and other
characteristics of the wound. The clinical course of wound healing was
assessed at specified intervals during the 3 month observation period.
Each wound was evaluated for wound healing, cosmetic appearance, and/or
general condition at 24 hrs, 1-2 weeks post treatment, and at 3 months
post treatment. Wound healing complications were noted as they appeared.

The trial was designed to compare the safety and efficacy of INDERMIL™
to traditional skin closure methods (sutures, staples, clips, and
adhesive strips). Patients with surgical incisions or lacerations of 8
cm or less were treated and assessed for complications (dehiscence,
infection, skin irritation), time to wound closure, and cosmesis
(cosmetic appearance of the wound after 3 months). One thousand
ninety-two (1,092) patients were randomized in 24 centers in the US and
Europe. These patients had a total of two thousand three hundred four
(2,304) wounds that could be evaluated. Patients were assessed at 24
hours after the procedure or at the time of discharge and at 1-2 weeks
for complications. They were assessed at 3 months following the
treatment for cosmesis. Complications at 1-2 weeks and cosmesis at 3
months were primary endpoints. Cosmesis was not assessed at the 1-2 week
interval.

The study population included patients who presented for simple skin
closure of wounds equal to or less than 8 cm. Patients or their legal
representative had to sign informed consent and agree to return for
follow-up visits. Patients were excluded if the tissue adhesive might
come into contact with blood vessels, had wounds under tension or over
joints, had known preoperative systemic infections or infections of the
site, had uncontrolled diabetes, or had diseases or conditions that are
known to interfere with the wound healing process.

[Patient ACCOUNTING, Demographics, AND WOUND
CHARACTERISTICS]{.underline}

A total of 1092 patients were randomized into the study from 24 sites.
Of the 1092 patients, 556 (50.9%) were randomized to the INDERMIL™
group, and 536 to the control group (49.1%). The 12 sites that had 40 or
more patients accounted for 83% of the patients studied.

Table 2 contains between-group comparisons of characteristics of the
randomly selected wounds.

Table 2:

Summary of Patient Accounting, Demographics, and Wound Characteristics

+---------------------------+---------+----------+---------+---------+
|                           | ***No   |          | ***With |         |
|                           | Subcu   |          | Subcu   |         |
|                           | ticular |          | ticular |         |
|                           | Sut     |          | Sut     |         |
|                           | ures*** |          | ures*** |         |
+---------------------------+---------+----------+---------+---------+
|                           | In      | Control  | In      | Control |
|                           | dermil™ |          | dermil™ |         |
+---------------------------+---------+----------+---------+---------+
|                           |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| ***Accounting***          |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| N, patients enrolled      | 346     | 326      | 210     | 210     |
+---------------------------+---------+----------+---------+---------+
| N, patients treated       | 346     | 326      | 210     | 210     |
|                           |         |          |         |         |
| N, wounds treated         | 925     | 820      | 281     | 278     |
+---------------------------+---------+----------+---------+---------+
| N, patients, control      |         | 294 / 32 |         | 126 /   |
| device:                   |         | / 18     |         | 20 / 83 |
| suture/strips/staples     |         |          |         |         |
| \*\*                      |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| N, wounds, control        |         | 741 /    |         | 185 /   |
| device:                   |         | 107 / 40 |         | 24 / 90 |
| suture/strips/staples\*\* |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| Patients completed:       | 98.6%   | 98.5%    | 99.5%   | 99.0%   |
|                           |         |          |         |         |
| 24 hour                   | 92.5%   | 87.7%    | 94.3%   | 93.8%   |
|                           |         |          |         |         |
| 7-14 days                 | 83.2%   | 79.4%    | 91.4%   | 88.5%   |
|                           |         |          |         |         |
| 80 -- 120 days            |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| ***Patient                | 3.5%    | 4.6%     | 0.0%    | 1.9%    |
| Demographics***           |         |          |         |         |
|                           | 9.5%    | 6.4%     | 2.4%    | 0.5%    |
| Age 0 - 4y                |         |          |         |         |
|                           | 64.7%   | 67.8%    | 54.1%   | 52.9%   |
| 5 - 18y                   |         |          |         |         |
|                           | 22.3%   | 21.2%    | 43.5%   | 44.7%   |
| 19 -- 60y                 |         |          |         |         |
|                           | 80.1%   | 81.3%    | 85.2%   | 88.6%   |
| \>60y                     |         |          |         |         |
|                           | 8.4%    | 8.9%     | 5.2%    | 6.7%    |
| Race White                |         |          |         |         |
|                           | 1.2%    | 0.6%     | 0.0%    | 0.0%    |
| Black                     |         |          |         |         |
|                           | 8.7%    | 5.8%     | 7.6%    | 3.3%    |
| Asian                     |         |          |         |         |
|                           | 1.7%    | 3.4%     | 1.9%    | 1.4%    |
| Hispanic                  |         |          |         |         |
|                           |         |          |         |         |
| Other                     |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| ***Wound                  | 1.5\*   | 1.7      | 4.3     | 4.5     |
| Characteristics***        |         |          |         |         |
|                           | 1.5     | 1.5      | 1.5     | 1.4     |
| Length in cm mean         |         |          |         |         |
|                           | 0.5     | 0.5      | 0.6     | 0.6     |
| Depth in cm mean          |         |          |         |         |
|                           | 66.8%   | 64.7%    | 87.9%   | 88.5%   |
| Width in cm mean          |         |          |         |         |
|                           | 31.4%   | 33.9%    | 11.7%   | 10.4%   |
| Class Clean               |         |          |         |         |
|                           | 1.8%    | 1.2%     | 0.4%    | 0.7%    |
| Clean-contaminated        |         |          |         |         |
|                           | 0.0%    | 0.2%     | 0.0%    | 0.4%    |
| Contaminated              |         |          |         |         |
|                           | 88.2%   | 87.9%    | 96.4%   | 95.7%   |
| Dirty                     |         |          |         |         |
|                           | 11.8%   | 12.1%    | 3.6%    | 4.3%    |
| Incisions                 |         |          |         |         |
|                           |         |          |         |         |
| Lacerations               |         |          |         |         |
+---------------------------+---------+----------+---------+---------+
| ***Use of Anesthesia***   | 137     | 121      |         |         |
|                           | (40%)   | (37%)    |         |         |
| General                   |         |          |         |         |
|                           | 121     | 196      |         |         |
| Local only                | (35%)\* | (60%)    |         |         |
|                           |         |          |         |         |
| None                      | 88      | 9 (3%)   |         |         |
|                           | (25%)   |          |         |         |
+---------------------------+---------+----------+---------+---------+

\* Differences between Indermil and Control were statistically
significant (p\< 0.05).

\*\* Several patients/ wounds were treated with more than one control
device.

The data show that the only statistically significant between-group
difference in the physical size of the wounds was in mean wound length
in the No Subcuticular Suture Group (NSS). There were no between-group
differences in numbers of patients enrolled; numbers of control devices
between NSS and With Subcuticular Suture (WSS); numbers of patients
completed at each time period; age; race; in the classification of the
wound as clean, clean-contaminated, contaminated, or dirty; the use of
anesthesia; or in the frequency with which subcutaneous sutures were
used for closure.

Clinical characteristics of the sample are detailed in Table 3, both for
the entire study population and by treatment arm. The table also
contains data on vital signs such as heart rate and blood pressure.
Entries are percentages or mean [+]{.underline} standard deviation.

Table3:

Clinical Parameters

  ------------------- ----------------- -------------------- --------------------- -------------
  **Variable**        **Entire sample** **INDERMIL™ group**  **Control group**     **P-value**

  Age years           47.7              47.4 [+]{.underline} 48.0 [+]{.underline}  0.589
                      [+]{.underline}   21                   20                    
                      20                                                           

  Male gender         52.1%             51.8%                52.5%                 0.813

  Body mass index     26.7              26.7                 26.7 [+]{.underline}  0.994
  (kg/m^2^            [+]{.underline}   [+]{.underline}5.7   5.6                   
                      5.7                                                          

  Body temperature    97.8              97.8 [+]{.underline} 97.8 [+]{.underline}  0.947
  (°F)                [+]{.underline}   0.9                  1.0                   
                      0.9                                                          

  Heart rate          76.4              76.0 [+]{.underline} 76.6 [+]{.underline}  0.560
  (beats/min.)        [+]{.underline}   13                   14                    
                      13                                                           

  Systolic blood      132               132 [+]{.underline}  132 [+]{.underline}   0.833
  pressure mm/Hg      [+]{.underline}   22                   22                    
                      22                                                           

  Diastolic blood     76.5              76.2 [+]{.underline} 76.8 [+]{.underline}  0.459
  pressure mm/Hg      [+]{.underline}   13                   12                    
                      12                                                           

  Respiration rate    16.7              16.9 [+]{.underline} 16.7[+]{.underline}   0.776
  breaths/min         [+]{.underline}   2.7                  2.9                   
                      2.8                                                          
  ------------------- ----------------- -------------------- --------------------- -------------

^1^Generated by chi square test after collapsing Asians and Hispanics
into the \"Other\" category.

[Patient Accounting or Disposition]{.underline}

Of the 1092 patients who entered the study, 171 (15.6%) discontinued
participation prematurely. The premature discontinuation rate was 13.8%
in the INDERMIL™ group and 17.5% in the control group. Table 4 contains
a summary of the reasons for premature discontinuation. Because there
was sometimes more than one reason for discontinuation, the individual
reasons add up to more than the total number of premature
discontinuations. The data indicate that the most common reasons for
premature discontinuation were non-compliance (60.2%), the inability of
the investigator to locate the patient (20.5%), and voluntary withdrawal
(12.9%). For the purposes of this study, noncompliance was the category
that was used for dropouts who failed to return for the final cosmesis
evaluation at 3 months despite efforts to bring them in for follow-up
(in accordance with the protocol).

Table 4:

Reasons for Premature Discontinuation of Study Participation

+----------------+-----------------+-----------------+-----------------+
| **Reason for   | **All           | **INDERMIL™     | **Control       |
| dropping out** | dropouts**      | group**         | group**         |
|                |                 |                 |                 |
|                | **(N = 171)**   | **(N = 77)**    | **(N = 94)**    |
+----------------+-----------------+-----------------+-----------------+
| Voluntary      | 12.9% (N = 22)  | 9.1% (n = 7)    | 16.0% (N = 15)  |
| withdrawal     |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+
| Non            | 60.2% (N = 103) | 59.7% (N = 46)  | 60.6% (N = 57)  |
| compliance\*   |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+
| Unable to      | 20.5% (N = 35)  | 27.3% (N = 21)  | 14.9% (N = 14)  |
| locate patient |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+
| Adverse event  | 4.7% (N = 8)    | 3.9% (N = 3)    | 5.3% (N = 5)    |
+----------------+-----------------+-----------------+-----------------+
| Patient died   | 3.5% (N = 6)    | 5.2% (N = 4)    | 2.1% (N = 2)    |
+----------------+-----------------+-----------------+-----------------+
| Terminated for | 7.6% (N = 13)   | 2.6% (N = 2)    | 11.7% (N = 11)  |
| other reasons  |                 |                 |                 |
+----------------+-----------------+-----------------+-----------------+

\* Noncompliance was reason given when patients failed to return for
final follow-ups.

Reasons for premature discontinuation were similar in the two groups
with the exception that "inability to locate the patient" was a more
common problem in the INDERMIL™ group (27.3%) than in the control group
(14.9%). There were a total of 6 deaths, 4 in the INDERMIL™ group and 2
in the control group. No deaths were device related. There was no
evidence of between-group differences for any variables.

[STUDY RESULTS]{.underline}

**VII. ADVERSE EFFECTS**

The following adverse events were reported in a prospective,
multicenter, randomized study of 1,092 patients and 2,304 wound. The
control group received sutures, staples, and adhesive strips.

Table 1:

Clinical Study Adverse Reactions

+--------------------+-------------+------------+-----------+----------+
| ***Adverse         | ***No       |            | ***With   |          |
| Reactions observed | S           |            | Sub       |          |
| at 10-14 days,***  | ubcuticular |            | cuticular |          |
|                    | Sutures     |            | Sutures   |          |
| ***per wound       | (NSS)***    |            | (WSS)***  |          |
| evaluated***       |             |            |           |          |
+--------------------+-------------+------------+-----------+----------+
|                    | Indermil™   | Control    | Indermil™ | Control  |
+--------------------+-------------+------------+-----------+----------+
| N, patients        | 346         | 326        | 210       | 210      |
| treated            |             |            |           |          |
|                    | 925         | 820        | 281       | 278      |
| N, wounds treated  |             |            |           |          |
+--------------------+-------------+------------+-----------+----------+
| *Dehiscence        | 30/853      | 9/709      | 4/253     | 2/257    |
| (Overall)\*\**     | (3.5%)\*    | (1.3%)     | (1.6%)    | (0.8%)   |
|                    |             |            |           |          |
| > *Not requiring   | 28/853      | 6/709      | 3/253     | 1/257    |
| > treatment*       | (3.2%)\*    | (0.9%)     | (1.2%)    | (0.4%)   |
|                    |             |            |           |          |
| *Requiring         | 2/853       | 3/709      | 1/253     | 1/257    |
| treatment*         | (0.2%)      | (0.4%)     | (0.4%)    | (0.4%)   |
|                    |             |            |           |          |
| *With infection*   | 2/853       | 1/709      | 0/253     | 0/257    |
|                    | (0.2%)      | (0.1%)     | (0.0%)    | (0.0%)   |
| *By wound class:*  |             |            |           |          |
|                    | 23/564      | 4/436      | 4/222     | 2/226    |
| *Clean*            | (4.1%)      | (0.9%)     | (1.8%)    | (0.9%)   |
|                    |             |            |           |          |
| *C                 | 7/273       | 3/261      | 0/31      | 0/29     |
| lean-contaminated* | (2.6%)      | (1.1%)     | (0.0%)    | (0.0%)   |
|                    |             |            |           |          |
| *Contaminated*     | 0/16 (0.0%) | 2/10       | none      | 0/2      |
|                    |             | (20.0%)    |           | (0.0%)   |
| *Dirty*            | none        |            | none      |          |
|                    |             | 0/2 (0.0%) |           | none     |
+--------------------+-------------+------------+-----------+----------+
| *Infection\*\*\**  | 5/853       | 4/709      | 1/253     | 3/257    |
|                    | (0.6%)      | (0.6%)     | (0.4%)    | (1.2%)   |
+--------------------+-------------+------------+-----------+----------+
| *Acute             |             |            |           |          |
| Inflammation*      |             |            |           |          |
+--------------------+-------------+------------+-----------+----------+
| Erythema           | 102/852     | 85/709     | 19/254    | 17/256   |
|                    | (12.0%)     | (12.0%)    | (7.5%)    | (6.6%)   |
+--------------------+-------------+------------+-----------+----------+
| Edema              | 23/853      | 18/707     | 6/253     | 15/256   |
|                    | (2.7%)      | (2.5%)     | (2.4%)\*  | (5.9%)   |
+--------------------+-------------+------------+-----------+----------+
| Hypersensitivity   | 6/853       | 1/706      | 0/254     | 2/256    |
|                    | (0.7%)      | (0.1%)     | (0.0%)    | (0.8%)   |
+--------------------+-------------+------------+-----------+----------+
| Drainage           | 39/853      | 14/709     | 7/254     | 6/257    |
|                    | (4.6%)\*    | (2.0%)     | (2.8%)    | (2.3%)   |
+--------------------+-------------+------------+-----------+----------+
| Sinus Tracts       | 4/850       | 0/705      | 2/253     | 1/256    |
|                    | (0.5%)      | (0.0%)     | (0.8%)    | (0.4%)   |
+--------------------+-------------+------------+-----------+----------+

\* Differences between Indermil and Control were statistically
significant (p\< 0.05).

\*\* Dehiscence was defined as "any disruption in which the edge of the
skin wound separates sufficiently to expose subcutaneous tissues".

\*\*\* Infection was defined as "a purulent discharge from the wound, a
positive culture or microbial count for pathogen that can be
documented". Only two wounds met this criteria, all other "suspected
infections" were based solely on clinical observation.

There were 13 infections reported; 7 from the control group and 6 from
the test group. Based on these data there was no significant difference
in the rate of infections between the INDERMIL™ and control treatment
groups. There was a statistically significant difference between the
Indermil™ and Control groups in dehiscence rates (for both overall and
wounds not requiring treatment), presence of edema for the WSS group,
and presence of drainage for the NSS group. The difference between
overall dehiscence rates was 3.5% in the Indermil™ group and 1.3% in the
Control group for the NSS group.

The primary outcome variables of this study were Time to wound closure,
Complications (primarily dehiscence), and Cosmesis. Table 5 below
contains between-group comparisons of the outcome variables and of a
series of additional outcome measures.

**VIII. POTENTIAL ADVERSE EFFECTS**

In addition to the adverse events observed during the study, the
following adverse events may occur: bonding to unintended body areas or
tissues; discomfort due to heat generation; allergic reaction to the
adhesive; foreign body reaction; and chronic non-healing wound.

Table 5

Summary of Effectiveness Results Comparing Indermil™ to Sutures, Staples
and Adhesive Strips

+-----------------+------------+------------+------------+-----------+
| ***Clinical     | ***No      |            | ***With    |           |
| Study           | Su         |            | Su         |           |
| Outcomes***     | bcuticular |            | bcuticular |           |
|                 | Sutures    |            | Sutures    |           |
|                 | (NSS)***   |            | (WSS)***   |           |
+-----------------+------------+------------+------------+-----------+
|                 | Indermil™  | Control    | Indermil™  | Control   |
+-----------------+------------+------------+------------+-----------+
| *Dermal         | 823/853    | 700/709    | 249/253    | 255/257   |
| Apposition*     | (96.5%)\*  | (98.7%)    | (98.4%)    | (99.2%)   |
+-----------------+------------+------------+------------+-----------+
| *Immediate:     | 1/925      | 340/820    | 2/2        | 88/278    |
| Additional      | (0.1%)\*   | (41.5%)    | 81(0.7%)\* | (31.6%)   |
| Device*         |            |            |            |           |
|                 |            |            |            |           |
| *(Adhesive      |            |            |            |           |
| strips)*        |            |            |            |           |
+-----------------+------------+------------+------------+-----------+
| *Cosmesis @ 3   | 88.0\*     | 92.2       | 89.3       | 89.9      |
| months\*\**     |            |            |            |           |
|                 | 82.9       | 91.4       | 87.3       | 96.5      |
| VAS Score, 100= |            |            |            |           |
| (optimal)       |            |            |            |           |
|                 |            |            |            |           |
| Mean Score      |            |            |            |           |
|                 |            |            |            |           |
| All Wounds      |            |            |            |           |
|                 |            |            |            |           |
| Dehisced Wounds |            |            |            |           |
+-----------------+------------+------------+------------+-----------+
| *Median Time to | 0.6\*      | 1.0        | 1.1\*      | 2.2       |
| Close           |            |            |            |           |
| (               |            |            |            |           |
| minutes)\*\*\** |            |            |            |           |
+-----------------+------------+------------+------------+-----------+

\* Differences between Indermil and Control were statistically
significant (p\< 0.05).

\*\* Cosmesis: Visual Analog Scale (VAS); 3-month actual time range = 80
-- 120 days

\*\*\* Time to Close was measured from the initial apposition of wound
edges to the time of closure.

With the exception of time to wound closure and cosmesis, all outcome
measures reflect data collected at the 1-2 week assessments. Note that
there are statistically significant differences between the Control and
Indermil™ groups for Dermal Apposition (NSS), Immediate: Additional
Device (NSS and WSS), Cosmesis: All Wounds (NSS), and Median Time to
Close (NSS and WSS).

*Time to Close:*

The wounds treated with INDERMIL™ had a median time to close of 0.9
minutes (54 seconds) as compared to 1.6 minutes (1 minute 36 seconds) in
the control group. This represents a statistically significant shorter
time to closure for the INDERMIL™ group.

*Dehiscence:*

There was a statistically significant difference between the Indermil™
and Control groups in dehiscence rates (for both overall and wounds not
requiring treatment), presence of edema, and presence of drainage for
the NSS group. The statistically significant difference between overall
dehiscence rates was 3.5% in the Indermil™ group and 1.3% in the Control
group. This difference was not judged to be clinically significant.

*Cosmesis:*

The study data revealed that the Indermil™ group and Control group had
equivalent cosmetic results as measured using a 100-point visual analog
scale for dehisced wounds. There was a statistically significant
difference between Indermil™ and Control groups for All Wounds in the
NSS group (88.0% for Indermil vs. 92.2% for Control). The cosmesis
scores are comparable from a clinical perspective.

**XI. CONCLUSIONS DRAWN FROM THE STUDY**

The preclinical testing of biocompatibility, in-vitro and in-vivo
strength, and histological effects, and the clinical trial in over 1,000
patients, provide a reasonable assurance of safety and effectiveness.

The clinical study data suggest that INDERMIL™ has a clinically
comparable cosmesis to the comparator group with a clinically comparable
incidence of adverse events. Indermil™ patients had a statistically
higher dehiscence rate and faster time to wound closure than control
patients, but these differences are not judged to be clinically
significant.

**XII. GENDER BIAS**

No selection bias because of gender was identified during the review of
the submission and no significant gender differences were noted in the
clinical studies. The ratio of male to female patient enrollment in the
study was 52.1% male and 47.9% female and this is reflective of the type
and frequency of the wounds and their underlying distribution in the
general population.

**XIII. PANEL RECOMMENDATION**

Pursuant to section 515(c)(2) of the Food, Drug, and Cosmetic Act (the
Act) as amended by the Safe Medical Devices Act of 1990 this PMA was not
referred to the General and Plastic Surgery Panel and FDA advisory panel
for review and recommendation. This is because the information in this
PMA substantially duplicates information previously reviewed by this
panel.

**XIV.** **CDRH DECISION**

Based on the preclinical and clinical data in the PMA, CDRH determined
the data provide reasonable assurance that the device is safe and
effective when used in accordance with the labeling.

The applicant\'s manufacturing facility was inspected on November 7,
2001, and was found to be in compliance with the Quality System
Regulation (21 CFR 820).

FDA issued an approval order on May 22, 2002.

**XV. 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 Requirement and Restrictions: See the approval order.