# General Information

## Device generic name: Dermal Implant

## Device trade name: Artecoll™, PMMA/Collagen Implant

## Applicant's name and address

> ARTES MEDICAL, INC.
>
> 4660 La Jolla Village Drive, Suite 825
>
> San Diego, CA. 92122 USA

## PMA number\*

## Date of Panel recommendation\*

## Date of notice of approval to the applicant\*

(\*to be completed by FDA )

# Indications for Use

Artecoll is indicated for the correction of contour deficiencies of soft
tissue.

# Device Description

Artecoll is composed of PMMA microspheres, 30 to 42 microns in size,
suspended in a water based carrier gel composed of 3.5% bovine collagen,
96.5% buffered, isotonic water for injection including 0.3% lidocaine.

+------------------------------------+------------------+--------------+
| **0.5 cc syringe contains**        |                  |              |
+------------------------------------+------------------+--------------+
| **Polymethylmethacrylate**         | > 120 mg         |              |
+------------------------------------+------------------+--------------+
| 3.5% Bovine Collagen Solution      | > 0.4 cc         |              |
+------------------------------------+------------------+--------------+
| Bovine Collagen                    |                  | 3.5%         |
+------------------------------------+------------------+--------------+
| > Phosphate Buffer                 |                  | 2.7%         |
+------------------------------------+------------------+--------------+
| > Sodium Chloride                  |                  | 0.3%         |
+------------------------------------+------------------+--------------+
| > Lidocaine Hydrochloride          |                  | 0.3%         |
+------------------------------------+------------------+--------------+
| > Water for Injection              |                  | 93.2%        |
+------------------------------------+------------------+--------------+

# Contraindications, Warnings, and Precautions

## Contraindications

> Artecoll must not be injected if the patient has a positive response
> to the required Artecoll Test Implant. Refer to Artecoll Test Implant
> Package Insert for complete instructions for administration and
> evaluation of the test implant.
>
> Artecoll must not be used in patients with severe allergies manifested
> by a history of anaphylaxis, or history or presence of multiple severe
> allergies.
>
> Artecoll contains lidocaine and must not be used in patients with
> known lidocaine hypersensitivity.
>
> Artecoll must not be used in patients with a history of allergies to
> any bovine collagen products, including but not limited to injectable
> collagen, collagen implants, hemostatic sponges and collagen based
> sutures, because these patients are likely to have hypersensitivity to
> bovine collagen in Artecoll.
>
> Artecoll must not be used in patients undergoing or planning to
> undergo desensitization injections to meat products, as these
> injections can contain bovine collagen.
>
> Artecoll is contraindicated for use in breast augmentation, and for
> implantation into bone, tendon, ligament, or muscle.

## Warnings

> An Artecoll Test Implant must be administered and evaluated prior to
> soft tissue deficiency correction using Artecoll. Refer to Artecoll
> Test Implant Physician Package Insert.
>
> Artecoll must not be implanted into blood vessels. Implantation of
> Artecoll into dermal vessels may cause vascular occlusion, infarction,
> or embolic phenomena.
>
> Artecoll should be used with caution in patients with histories of
> allergic reactions to other substances, as injectable collagen use has
> been associated with allergic hypersensitivity responses, especially
> in patients with such histories.
>
> Use of Artecoll at specific sites in which an active inflammatory
> process (skin eruptions such as cysts, pimples, rashes, or hives) or
> infection is present should be deferred until the inflammatory process
> has been controlled.
>
> The safety of Artecoll for use during pregnancy, in breastfeeding
> females or in patients under 18 years has not been established.
>
> Artecoll should be used with caution in patients on immunosuppressive
> therapy.
>
> Patients who are using substances that interfere with platelet
> function or have any condition that reduces coagulation may experience
> increased bruising or bleeding at injection sites.

## Precautions

> The injection of Artecoll carries an inherent, yet minimal, risk of
> infection, as does any transcutaneous procedure. The usual precautions
> associated with injectable materials should be followed.
>
> After use, treatment syringes and needles may be potential biohazards.
> Handle accordingly and dispose of in accordance with accepted medical
> practice and applicable local, state and federal requirements.
>
> Artecoll has an opaque, off-white appearance. In the event that the
> content of a syringe shows signs of separation and/or appears clear
> (like water) after being melted, do not use the syringe and notify
> Artes Medical, Inc. at (858) 550-9999, or toll-free at (866) ARTESINC.

# Alternative Practices and Procedures

Alternatives to treatment with Artecoll may include:

-   no treatment

-   treatment with injectable bovine collagen fillers (Zyplast, Zyderm;
    McGhan Medical Corp., Santa Barbara, CA)

-   injection of processed cadaver tissue (Cymetra; Lifecell Corp., The
    Woodlands, TX) (Fascian; Fascia Biosystems, LLC, Beverly Hills, CA)

-   injection of autologous fat

-   injection of botulinum toxin (Botox; Allergan, Inc., Irvine, CA)

-   laser resurfacing

Of these alternatives, treatment with injectable bovine collagen fillers
that do not contain PMMA microspheres has been shown to require
retreatment at regular intervals to maintain the desired effect.
Processed cadaver tissue is estimated to last three to six months.
Autologous fat injections need to be repeated because only a low
percentage (\<5%) of implanted cells find connection to subcutaneous
capillaries of the recipient bed, which is essential for transplant
survival. Botulinum toxin injections paralyze the movement of facial
muscles for three to six months. They are regarded as safe, but are
intended for use only in the upper face. Laser resurfacing can reduce
the fine lines and wrinkles that may result from skin aging, but is not
intended for treatment of the deep folds for which Artecoll is
indicated.

# Marketing History

The predecessor of Artecoll, Arteplast (PMMA microspheres suspended in
gelatin), was developed in Frankfurt, Germany in 1989 and was used in
clinical trials in over 600 patients. In order to significantly reduce
the rate of side effects, Artecoll was developed, with a change in the
PMMA microsphere sieving procedure and use of collagen as a suspension
medium. Rofil Medical International B.V., Breda, The Netherlands, began
marketing Artecoll worldwide (not in the U.S.) in 1994. In September
1996, Artecoll was certified for the CE mark as a Class III medical
device. Artecoll was approved in Canada in September 1998, and is
marketed by Canderm Pharma, St Laurent, QC. In Mexico, approval was
granted May 1999, and the device is marketed by Grupo Venta Int.,
Guadalajara, Jal.

# Potential Adverse Effects of the Device on Health

No implant-related severe illness, trauma or death occurred among the
subjects treated with either Artecoll or the commercially available
Control implants in the clinical studies described in Section IX. The
Artecoll open label U.S. clinical trial included 157 subjects. One-year
safety evaluations were available for 126 subjects. The Artecoll
controlled, randomized U.S. clinical trial involved 128 subjects treated
with Artecoll and 123 subjects treated with either of two commercially
available Control implants. For the controlled, randomized trial,
follow-up periods for both safety and efficacy were at one, three and
six months, with a final 12-month safety evaluation.

## Observed Adverse Events

> Table 1 reports all of the adverse events (treatment-related and
> non-treatment-related) reported for Artecoll and the established
> Control group subjects during the controlled, randomized trial, in
> order of reported frequency for Artecoll group subjects. Table 2
> reports all of the adverse events (treatment-related and
> non-treatment-related) reported for Artecoll subjects during the open
> label trial, in order of reported frequency.

TABLE 1.

Adverse events reported in controlled, randomized clinical trial of
Artecoll

<table>
<colgroup>
<col style="width: 23%" />
<col style="width: 7%" />
<col style="width: 10%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 11%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 10%" />
<col style="width: 0%" />
<col style="width: 8%" />
<col style="width: 11%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="4">Event</td>
<td colspan="11">Number of Events</td>
</tr>
<tr class="even">
<td colspan="5">Artecoll</td>
<td colspan="6">Control</td>
</tr>
<tr class="odd">
<td colspan="4">Severity of Event, as determined by investigator</td>
<td rowspan="2">Removal or Drainage*</td>
<td colspan="5">Severity of Event, as determined by investigator </td>
<td rowspan="2"><p>Removal or</p>
<p>Drainage*</p></td>
</tr>
<tr class="even">
<td>Mild</td>
<td>Moderate</td>
<td colspan="2">Severe</td>
<td colspan="2">Mild</td>
<td colspan="2">Moderate</td>
<td>Severe</td>
</tr>
<tr class="odd">
<td>Lumpiness at injection area more than one month after injection</td>
<td><p>6(1**)</p>
<p>(1****)</p></td>
<td>2</td>
<td colspan="2">0</td>
<td>1*** (mild)</td>
<td>1</td>
<td colspan="2">1</td>
<td colspan="2">2</td>
<td></td>
</tr>
<tr class="even">
<td>Persistent swelling or redness</td>
<td>5</td>
<td>2</td>
<td colspan="2">0</td>
<td></td>
<td>9(1****)</td>
<td colspan="2">3</td>
<td colspan="2">1</td>
<td></td>
</tr>
<tr class="odd">
<td>Increased sensitivity</td>
<td>4</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">1</td>
<td></td>
</tr>
<tr class="even">
<td>Rash, itching more than 48 hours after injection</td>
<td>2</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">2</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="odd">
<td>Blurred vision</td>
<td>0</td>
<td>1</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="even">
<td>Flu-like symptoms</td>
<td>0</td>
<td>1</td>
<td colspan="2">0</td>
<td></td>
<td>1****</td>
<td colspan="2">0</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="odd">
<td>Recurrence of existing herpes labialis</td>
<td>1</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="even">
<td>Sensitization reactions</td>
<td>0</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>2</td>
<td colspan="2">3</td>
<td colspan="2">1</td>
<td></td>
</tr>
<tr class="odd">
<td>Abscess</td>
<td>0</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">1</td>
<td colspan="2">2</td>
<td>2 (severe)</td>
</tr>
<tr class="even">
<td>Visibility of puncture area</td>
<td>0</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">2</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="odd">
<td>Granuloma or enlargement of the implant</td>
<td>0</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">1</td>
<td></td>
</tr>
<tr class="even">
<td>Infection</td>
<td>0</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">1</td>
<td></td>
</tr>
<tr class="odd">
<td>Other local complications</td>
<td>1</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>1****</td>
<td colspan="2">0</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="even">
<td>Other systemic complications</td>
<td>0</td>
<td>1****</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">0</td>
<td></td>
</tr>
<tr class="odd">
<td>Severe illness, trauma, death</td>
<td>0</td>
<td>0</td>
<td colspan="2">0</td>
<td></td>
<td>0</td>
<td colspan="2">0</td>
<td colspan="2">1****</td>
<td></td>
</tr>
<tr class="even">
<td rowspan="2">Total AEs</td>
<td>19</td>
<td>7</td>
<td>0</td>
<td colspan="2" rowspan="2">1</td>
<td>14</td>
<td colspan="3">12</td>
<td>10</td>
<td>2</td>
</tr>
<tr class="odd">
<td colspan="3">26</td>
<td colspan="5">36</td>
<td></td>
</tr>
<tr class="even">
<td>Total subjects with AEs</td>
<td colspan="4">21</td>
<td>1</td>
<td colspan="5">16</td>
<td>2</td>
</tr>
<tr class="odd">
<td>Total subjects treated</td>
<td colspan="5">128</td>
<td colspan="6">123</td>
</tr>
<tr class="even">
<td>% of subjects with AEs</td>
<td colspan="4">16.4</td>
<td>0.8</td>
<td colspan="5">13.0</td>
<td>1.6</td>
</tr>
</tbody>
</table>

\* AEs with removal or drainage are included in Mild/Moderate/Severe
counts

\*\* Used contrary to protocol (lip augmentation)

\*\*\* Pathology showed no foreign body reaction. Diagnosis, seborrheic
keratosis. Not related to implant

\*\*\*\* Not related to implant

TABLE 2.

Adverse events reported in open label trial of Artecoll

  ------------------------ -------------- ---------- --------- --------- ----------------
  Event                    Number of                                     
                           Events                                        

                           Severity of                                   Removal or
                           Event, as                                     Drainage\*
                           determined by                                 
                           investigator                                  

                           Mild           Moderate   Severe    Unknown   

  Lumpiness at injection   1              1\*\*      0         3         1 (moderate)\*\*
  area \> one month after                                                
  injection                                                              

  Persistent swelling or   2              0          0         1         
  redness                                                                

  Increased sensitivity    0              0          0         1         

  Rash, itching more than  2              0          0                   
  48 hours after injection                                               

  Sensitization reactions  1              0          0         1         

  Granuloma or enlargement 0              0          1                   1
  of the implant                                                         

  Other local              0              1\*\*\*    0         1\*\*\*   
  complications                                                          

  Other systemic           1\*\*\*        0          0                   
  complications                                                          

  Severe illness, trauma,  0              0          1\*\*\*             
  death                                                                  

  Total AEs                7              2          2         7         2

                           18                                            

  Total subjects with AEs  17                                            2

  Total subjects evaluated 126                                           126

  \% of subjects with AEs  13.5                                          1.6
  ------------------------ -------------- ---------- --------- --------- ----------------

\* AEs with removal or drainage are included in
Mild/Moderate/Severe/Unknown counts

\*\* Used contrary to protocol (lip augmentation)

\*\*\*Not related to implant

## Potential Adverse Events

> Based on the literature and experience with Artecoll outside the
> United States, possible adverse events that might occur but have not
> been reported in the U.S. clinical trial include hypersensitivity to
> bovine collagen, nodule formation, infection, abscess, and possible
> vascular occlusion. In case of lumpiness due to displacement of
> implant or late granuloma formation, the treatment of choice is
> multiple triamcinolone acetonide injections intralesionally (1).

# Summary of Preclinical Studies

## Laboratory Studies

## Morhenn, et. al. , conducted an experimental study at the University of California, San Diego to determine which sizes of polymethylmethacrylate (PMMA) microspheres are phagocytosed by three human cell lines in tissue culture (2). Human macrophages U-937, Langerhans cells XS 106 and XS 52, and human keratinocytes HaCaT were able to phagocytose PMMA microspheres 20 μm or smaller. Microspheres larger than 20 μm were not ingested by any cell line. Microparticles made of silicone or polymethacrylate, on the other hand, were phagocytosed, possibly because of their different physical shape. {#morhenn-et.-al.-conducted-an-experimental-study-at-the-university-of-california-san-diego-to-determine-which-sizes-of-polymethylmethacrylate-pmma-microspheres-are-phagocytosed-by-three-human-cell-lines-in-tissue-culture-2.-human-macrophages-u-937-langerhans-cells-xs-106-and-xs-52-and-human-keratinocytes-hacat-were-able-to-phagocytose-pmma-microspheres-20-μm-or-smaller.-microspheres-larger-than-20-μm-were-not-ingested-by-any-cell-line.-microparticles-made-of-silicone-or-polymethacrylate-on-the-other-hand-were-phagocytosed-possibly-because-of-their-different-physical-shape. .unnumbered}

## Animal Studies

> G. Lemperle, et. al., in a study conducted at the University of
> Frankfurt, demonstrated in experiments on rats the safety and
> biocompatibility of PMMA microspheres (3). Histological specimens up
> to seven months after intradermal and subdermal implantation revealed
> a modest tissue reaction, forming a delicate fibrous capsule around
> each individual microsphere. No breakdown, corrosion, phagocytosis or
> migration of the spheres was observed at seven months.
>
> In another experimental study at the University of California, San
> Diego, ten soft tissue filler substances, which were widely used
> outside the U.S., were injected subdermally in mice (4). At one,
> three, six and nine months, implantation sites were excised and
> microscopically inspected together with local lymph nodes, lungs,
> liver and spleen. The different materials caused different patterns of
> foreign body reactions, which were examined according to the Duranti
> classification. The least tissue reaction around particulate material
> was observed in the Artecoll implants. In mice, no migration or
> transportation of any of the injected particulate filler substances to
> lymph nodes or filter organs could be detected at any of the four time
> points. Apparently, macrophages with high numbers of phagocytosed
> small microspheres or particles were unable to migrate to lymph nodes
> or filter organs.

[]{.mark}

# Summary of Clinical Studies

## Controlled, Randomized Trial

### Study design

> The Artecoll clinical trial was a prospective, multi-center,
> controlled, randomized, double-masked trial. Subjects were randomized
> (1:1) to either Artecoll or a commercially available collagen implant
> (Zyderm 2 for glabellar folds, Zyplast for others, collectively
> termed "Control").

#### Primary Objectives

-   To determine whether the cosmetic correction provided by Artecoll at
    the end of a six month period following injection is superior to
    that provided by a commercially available collagen implant at the
    same time period

-   To determine the safety of Artecoll as an injectable implant for
    correction of contour deformities of the dermis of the face

#### Secondary Objectives

-   To characterize the initial quality of the cosmetic correction
    provided by Artecoll and the commercially available collagen implant

-   To characterize investigator assessment of success with respect to
    how closely the treatment met the investigator's initial
    expectations for correction

-   To characterize subject assessment of satisfaction with respect to
    the subject's personal expectations

> A total of 251 subjects were injected with either Artecoll (128
> subjects) or with the the established Control device (123 subjects) at
> eight dermatology or plastic surgery centers in the U.S. Follow-up
> periods for both safety and efficacy were at one, three and six
> months, with a final 12-month safety evaluation.

### Patient assessment

> Treatment effectiveness was assessed at each follow-up visit.
> Photographs were taken at the time of pre-treatment evaluation and at
> each post-treatment evaluation. From the photographs, independent,
> masked observers classified each fold according to the Facial Fold
> Assessment (FFA) Scale, a scale that was created and validated for
> this study. Standardized reference photographs were used by the masked
> observers for comparison. For evaluation of secondary objectives,
> investigators rated success of treatment and subjects indicated
> satisfaction ratings.

### Demographic data

> Twenty-two men and 229 women between the ages of 28 and 82 were
> enrolled in the study. Study centers all were located in the U.S. The
> overall mean age was 52.2 years. The age distributions for the two
> treatment groups and the sample as a whole are summarized in Table 3.
> The groups did not differ significantly in mean age (t = 1.42, df =
> 249, p = .157).

Table 3.

Age distribution of subjects by treatment group

  -------------------- ---------------- ---------------- ----------------
  Treatment            Artecoll         Control          Total

  N                    128              123              251

  Mean                 53.2             51.2             52.2

  Std.Dev.             10.3             11.3             10.8

  Std.Err.             0.9              1.0              0.7

  Minimum              28               29               28

  Maximum              82               78               82

  Range                54               49               54

  Variance             105.6            128.3            117.2
  -------------------- ---------------- ---------------- ----------------

> The gender distributions for the two treatment groups and for the
> sample as a whole are summarized in Table 4. Most of the subjects
> treated (91.2%) were female. The gender distribution did not differ
> significantly between treatment groups (Yates corrected
> chi‑square = 0.00, p=1.000).

Table 4.

Gender distribution of subjects by treatment group

  ---------- ---------- ---------- ---------- ---------- ---------- ---------
  Gender     Artecoll              Control               Total      

             Number     Percent    Number     Percent    Number     Percent

  Male       11         8.6%       11         8.9%       22         8.8%

  Female     117        91.4%      112        91.1%      229        91.2%
  ---------- ---------- ---------- ---------- ---------- ---------- ---------

### Data analysis and results

#### Primary objectives

> For the first primary objective, the comparison of Artecoll and
> Control in terms of improvement in masked observer FFA Scale ratings
> at the 6-month follow-up observation was completed using Mann-Whitney
> U tests since improvement data were not normally distributed. The
> results for objective 1 are summarized in Table 5. The difference for
> Nasolabial Folds was statistically significant. The means and mean
> ranks indicate that Artecoll treatment resulted in greater improvement
> than Control in these cases. Thus, the alternative hypothesis was
> accepted for Nasolabial Folds. There were no significant differences
> between Artecoll and Control for Glabellar Folds, Upper Lip Lines, or
> Mouth Corners.

Table 5.

Improvement in masked observer FFA Scale ratings from pre-treatment to
six months for each fold area by treatment group -- Objective 1

  ------------ ----------- ----- ------- ---------- ------- ------- -------------- --------
  Treatment    Treatment   N     Mean    Std.Dev.   Std.    Mean    Mann-Whitney U 
  Area                                              Err.    Rank    Test           

                                                                    U              p

  Glabellar    Artecoll    71    0.34    0.79       0.09    75.4    2795.0         .971
  Folds                                                                            

               Control     79    0.32    0.68       0.08    75.6                   

  Nasolabial   Artecoll    92    0.77    0.87       0.09    113.8   2176.5         \<.001
  Folds                                                                            

               Control     91    0.00    0.90       0.09    69.9                   

  Upper Lip    Artecoll    55    0.08    0.62       0.08    49.2    1164.5         .176
  Lines                                                                            

               Control     50    0.22    0.48       0.07    57.2                   

  Mouth        Artecoll    69    0.26    0.76       0.09    78.3    2465.0         .316
  Corners                                                                          

               Control     79    0.07    0.74       0.08    71.2                   
  ------------ ----------- ----- ------- ---------- ------- ------- -------------- --------

> For the second primary objective, that is, total number of subjects
> with any adverse events, Artecoll and Control were compared using the
> chi-square test with correction for continuity. The result was not
> significant (chi‑square=0.338, p=.561) indicating that the two
> treatments did not differ in adverse event rates.
>
> Only one Artecoll and two Control subjects required follow-up removal
> or drainage. The treatment difference in this rate is not significant
> (Fisher Exact Test p = .485). A total of 128 subjects received
> Artecoll injections. No unanticipated adverse device effects were
> reported. Adverse events reported for the Artecoll subjects were
> similar to but lower in number than the adverse events reported for
> the Control group. No implant-related severe illness, trauma or death
> occurred among the subjects treated with either Artecoll or the
> Control implant.

#### Secondary objectives

> The quality of the initial treatment result was characterized using
> the FFA Scale at one month and three months post-treatment, comparing
> severity with pre-treatment ratings. The initial quality of the
> cosmetic correction provided by Artecoll and Control was compared by
> use of non-parametric Mann-Whitney U tests. Using masked observer FFA
> Scale ratings, improvement from pretreatment values at one month was
> greater for Control than for Artecoll for Glabellar Folds and not
> significantly different between treatment groups for the other
> treatment areas. By three months, improvement was greater for Artecoll
> than for Control for Nasolabial Folds and for Mouth Corners and the
> treatment groups were not significantly different for the other
> treatment areas.
>
> Table 6 summarizes the initial progress at one month post-treatment.
> The difference in improvement between Artecoll and Control was
> significant for Glabellar Folds. Means and mean ranks indicate that
> this initial improvement was greater for Control than for Artecoll. No
> other treatment area showed a significant difference between Artecoll
> and Control.

Table 6.

Improvement in masked observer FFA Scale ratings from pre-treatment to
one month

+-----------+--------+---+-----+------+------+------+--------+------+
| Treatment | Tre    | N | M   | Std. | Std. | Mean | Mann-W |      |
| Area      | atment |   | ean | Dev. | Err. |      | hitney |      |
|           |        |   |     |      |      | Rank | Test   |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           |        |   |     |      |      |      | U      | p    |
+-----------+--------+---+-----+------+------+------+--------+------+
| Glabellar | Ar     | 6 | 0   | 0.69 | 0.09 | 60.3 | 1777.5 | .004 |
| Folds     | tecoll | 4 | .17 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 7 | 0   | 0.68 | 0.08 | 79.9 |        |      |
|           | ontrol | 7 | .49 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
| N         | Ar     | 9 | 0   | 0.76 | 0.08 | 92.9 | 4010.0 | .713 |
| asolabial | tecoll | 1 | .75 |      |      |      |        |      |
| Folds     |        |   |     |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 9 | 0   | 0.73 | 0.08 | 92.1 |        |      |
|           | ontrol | 1 | .74 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
| Upper Lip | Ar     | 5 | 0   | 0.55 | 0.07 | 52.3 | 1323.0 | .205 |
| Lines     | tecoll | 8 | .31 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 5 | 0   | 0.60 | 0.08 | 60.0 |        |      |
|           | ontrol | 3 | .48 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
| Mouth     | Ar     | 7 | 0   | 0.72 | 0.09 | 78.9 | 2351.5 | .179 |
| Corners   | tecoll | 1 | .46 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 7 | 0   | 0.65 | 0.07 | 69.4 |        |      |
|           | ontrol | 6 | .30 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+

> Table 7 summarizes the progress at three months post-treatment. The
> difference in improvement between Artecoll and Control was significant
> for Nasolabial Folds and Mouth Corners. Means and mean ranks indicate
> that improvement at three months was greater for Artecoll than for
> Control. The other treatment areas showed no significant difference
> between Artecoll and Control.

Table 7.

Improvement in masked observer FFA Scale ratings from pre-treatment to
three months

+-----------+--------+---+-----+------+------+------+--------+------+
| Treatment | Tre    | N | M   | Std. | Std. | Mean | Mann-W |      |
| Area      | atment |   | ean | Dev. | Err. |      | hitney |      |
|           |        |   |     |      |      | Rank | Test   |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           |        |   |     |      |      |      | U      | p    |
+-----------+--------+---+-----+------+------+------+--------+------+
| Glabellar | Ar     | 6 | 0   | 0.80 | 0.10 | 67.1 | 2213.0 | .348 |
| Folds     | tecoll | 5 | .25 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 7 | 0   | 0.60 | 0.07 | 73.5 |        |      |
|           | ontrol | 5 | .35 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
| N         | Ar     | 8 | 0   | 0.81 | 0.09 | 1    | 2173.5 | \<   |
| asolabial | tecoll | 7 | .81 |      |      | 07.0 |        | .001 |
| Folds     |        |   |     |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 8 | 0   | 0.79 | 0.08 | 69.2 |        |      |
|           | ontrol | 8 | .15 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
| Upper Lip | Ar     | 5 | 0   | 0.64 | 0.09 | 50.3 | 1236.5 | .454 |
| Lines     | tecoll | 3 | .18 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 5 | 0   | 0.52 | 0.07 | 54.8 |        |      |
|           | ontrol | 1 | .25 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
| Mouth     | Ar     | 6 | 0   | 0.80 | 0.10 | 83.6 | 1657.5 | .001 |
| Corners   | tecoll | 4 | .45 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+
|           | C      | 7 | 0   | 0.66 | 0.07 | 60.5 |        |      |
|           | ontrol | 7 | .01 |      |      |      |        |      |
+-----------+--------+---+-----+------+------+------+--------+------+

> To determine investigator assessment of success with respect to how
> closely the treatment met the investigator's initial expectations for
> correction, the investigator's assessment (not masked) of success was
> rated using a five-point scale, with 1 corresponding to \"completely
> successful\" and 5 to \"not at all successful\", at one, three and six
> months post-treatment. Descriptive statistics were used to
> characterize the investigator ratings. Table 8 summarizes the findings
> and the means are illustrated in Figure 1. By month three, ratings
> that are more successful were obtained for Artecoll than for Control
> in each treatment area. Mean investigator ratings of Artecoll were
> roughly at the \"very successful\" level at all follow-up points. Mean
> investigator ratings of success for Artecoll treatment were in the
> \"very successful\" range at all follow-up points while less
> successful for Control at months three and six.

Table 8.

Investigator ratings of success for each treatment area at each
follow-up time

<table>
<colgroup>
<col style="width: 9%" />
<col style="width: 17%" />
<col style="width: 4%" />
<col style="width: 6%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><p>Time</p>
<p>(months)</p></td>
<td rowspan="2">Treatment Area</td>
<td colspan="5">Artecoll</td>
<td colspan="5">Control</td>
</tr>
<tr class="even">
<td>N</td>
<td><strong>Mean</strong></td>
<td><p>Std.</p>
<p>Dev.</p></td>
<td><p>Std.</p>
<p>Err.</p></td>
<td>Mean Rank</td>
<td>N</td>
<td><strong>Mean</strong></td>
<td><p>Std.</p>
<p>Dev.</p></td>
<td><p>Std.</p>
<p>Err.</p></td>
<td>Mean Rank</td>
</tr>
<tr class="odd">
<td rowspan="4">1</td>
<td>Glabellar Folds</td>
<td>68</td>
<td><strong>1.93</strong></td>
<td>0.94</td>
<td>0.11</td>
<td>74.82</td>
<td>79</td>
<td><strong>1.91</strong></td>
<td>1.00</td>
<td>0.11</td>
<td>73.30</td>
</tr>
<tr class="even">
<td>Nasolabial Folds</td>
<td>93</td>
<td><strong>1.99</strong></td>
<td>0.89</td>
<td>0.09</td>
<td>92.89</td>
<td>93</td>
<td><strong>2.06</strong></td>
<td>1.03</td>
<td>0.11</td>
<td>94.11</td>
</tr>
<tr class="odd">
<td>Upper Lip Lines</td>
<td>61</td>
<td><strong>1.88</strong></td>
<td>0.82</td>
<td>0.11</td>
<td>55.49</td>
<td>54</td>
<td><strong>2.02</strong></td>
<td>0.88</td>
<td>0.12</td>
<td>60.83</td>
</tr>
<tr class="even">
<td>Mouth Corners</td>
<td>74</td>
<td><strong>2.00</strong></td>
<td>0.97</td>
<td>0.11</td>
<td>66.91</td>
<td>77</td>
<td><strong>2.55</strong></td>
<td>1.28</td>
<td>0.15</td>
<td>84.73</td>
</tr>
<tr class="odd">
<td rowspan="4">3</td>
<td>Glabellar Folds</td>
<td>67</td>
<td><strong>2.02</strong></td>
<td>1.00</td>
<td>0.12</td>
<td>61.51</td>
<td>74</td>
<td><strong>2.68</strong></td>
<td>1.40</td>
<td>0.16</td>
<td>79.59</td>
</tr>
<tr class="even">
<td>Nasolabial Folds</td>
<td>89</td>
<td><strong>1.90</strong></td>
<td>0.87</td>
<td>0.09</td>
<td>68.08</td>
<td>89</td>
<td><strong>3.07</strong></td>
<td>1.41</td>
<td>0.15</td>
<td>110.92</td>
</tr>
<tr class="odd">
<td>Upper Lip Lines</td>
<td>58</td>
<td><strong>2.04</strong></td>
<td>0.90</td>
<td>0.12</td>
<td>43.58</td>
<td>51</td>
<td><strong>3.11</strong></td>
<td>1.39</td>
<td>0.20</td>
<td>67.99</td>
</tr>
<tr class="even">
<td>Mouth Corners</td>
<td>68</td>
<td><strong>2.08</strong></td>
<td>0.94</td>
<td>0.11</td>
<td>51.85</td>
<td>76</td>
<td><strong>3.38</strong></td>
<td>1.34</td>
<td>0.15</td>
<td>90.97</td>
</tr>
<tr class="odd">
<td rowspan="4">6</td>
<td>Glabellar Folds</td>
<td>74</td>
<td><strong>2.06</strong></td>
<td>1.07</td>
<td>0.12</td>
<td>57.91</td>
<td>82</td>
<td><strong>3.43</strong></td>
<td>1.51</td>
<td>0.17</td>
<td>97.09</td>
</tr>
<tr class="even">
<td>Nasolabial Folds</td>
<td>97</td>
<td><strong>1.73</strong></td>
<td>0.69</td>
<td>0.07</td>
<td>58.87</td>
<td>96</td>
<td><strong>4.05</strong></td>
<td>1.32</td>
<td>0.13</td>
<td>135.53</td>
</tr>
<tr class="odd">
<td>Upper Lip Lines</td>
<td>60</td>
<td><strong>1.98</strong></td>
<td>0.93</td>
<td>0.12</td>
<td>36.76</td>
<td>54</td>
<td><strong>4.13</strong></td>
<td>1.28</td>
<td>0.17</td>
<td>80.55</td>
</tr>
<tr class="even">
<td>Mouth Corners</td>
<td>73</td>
<td><strong>2.19</strong></td>
<td>0.98</td>
<td>0.12</td>
<td>48.95</td>
<td>81</td>
<td><strong>4.09</strong></td>
<td>1.32</td>
<td>0.15</td>
<td>103.23</td>
</tr>
</tbody>
</table>

> ![](media/image1.wmf)
>
> To determine subject assessment of satisfaction with respect to the
> subject's personal expectations, the subject's assessment (masked) of
> satisfaction was rated using a five-point scale, with 1 corresponding
> to \"very satisfied\" and 5 to \"very dissatisfied,\" at one, three
> and six months post-treatment. Descriptive statistics were used to
> characterize the satisfaction ratings. Table 9 summarizes the findings
> and the means are illustrated in Figure 2. By month three, more
> "satisfied" ratings were obtained for Artecoll than for the
> established Control implants in each treatment area. Mean satisfaction
> ratings for Artecoll were roughly at the \"satisfied\" level at all
> follow-up points while subjects showed lower satisfaction with Control
> at months three and six.

Table 9.

Subject ratings of satisfaction for each treatment area at each
follow-up point

<table>
<colgroup>
<col style="width: 11%" />
<col style="width: 18%" />
<col style="width: 5%" />
<col style="width: 8%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 8%" />
<col style="width: 6%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
<col style="width: 7%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="2"><p>Time</p>
<p>(months)</p></td>
<td rowspan="2">Treatment Area</td>
<td colspan="5">Artecoll</td>
<td colspan="5">Control</td>
</tr>
<tr class="even">
<td>N</td>
<td><strong>Mean</strong></td>
<td><p>Std.</p>
<p>Dev.</p></td>
<td><p>Std.</p>
<p>Err.</p></td>
<td>Mean Rank</td>
<td>N</td>
<td><strong>Mean</strong></td>
<td><p>Std.</p>
<p>Dev.</p></td>
<td><p>Std.</p>
<p>Err.</p></td>
<td>Mean Rank</td>
</tr>
<tr class="odd">
<td rowspan="4">1</td>
<td>Glabellar Folds</td>
<td>70</td>
<td><strong>1.92</strong></td>
<td>0.99</td>
<td>0.12</td>
<td>73.75</td>
<td>82</td>
<td><strong>2.02</strong></td>
<td>0.98</td>
<td>0.11</td>
<td>78.85</td>
</tr>
<tr class="even">
<td>Nasolabial Folds</td>
<td>95</td>
<td><strong>1.88</strong></td>
<td>1.04</td>
<td>0.11</td>
<td>91.85</td>
<td>98</td>
<td><strong>2.02</strong></td>
<td>0.96</td>
<td>0.10</td>
<td>101.99</td>
</tr>
<tr class="odd">
<td>Upper Lip Lines</td>
<td>64</td>
<td><strong>1.96</strong></td>
<td>1.07</td>
<td>0.13</td>
<td>59.34</td>
<td>57</td>
<td><strong>2.07</strong></td>
<td>1.09</td>
<td>0.14</td>
<td>62.86</td>
</tr>
<tr class="even">
<td>Mouth Corners</td>
<td>77</td>
<td><strong>2.08</strong></td>
<td>0.98</td>
<td>0.11</td>
<td>72.71</td>
<td>83</td>
<td><strong>2.44</strong></td>
<td>1.12</td>
<td>0.12</td>
<td>87.72</td>
</tr>
<tr class="odd">
<td rowspan="4">3</td>
<td>Glabellar Folds</td>
<td>64</td>
<td><strong>2.20</strong></td>
<td>1.15</td>
<td>0.14</td>
<td>61.30</td>
<td>73</td>
<td><strong>2.72</strong></td>
<td>1.38</td>
<td>0.16</td>
<td>75.75</td>
</tr>
<tr class="even">
<td>Nasolabial Folds</td>
<td>88</td>
<td><strong>2.14</strong></td>
<td>1.08</td>
<td>0.12</td>
<td>76.16</td>
<td>89</td>
<td><strong>2.81</strong></td>
<td>1.34</td>
<td>0.14</td>
<td>101.70</td>
</tr>
<tr class="odd">
<td>Upper Lip Lines</td>
<td>55</td>
<td><strong>2.13</strong></td>
<td>1.07</td>
<td>0.14</td>
<td>42.64</td>
<td>50</td>
<td><strong>3.09</strong></td>
<td>1.34</td>
<td>0.19</td>
<td>64.40</td>
</tr>
<tr class="even">
<td>Mouth Corners</td>
<td>66</td>
<td><strong>2.24</strong></td>
<td>1.06</td>
<td>0.13</td>
<td>57.53</td>
<td>75</td>
<td><strong>3.05</strong></td>
<td>1.31</td>
<td>0.15</td>
<td>82.85</td>
</tr>
<tr class="odd">
<td rowspan="4">6</td>
<td>Glabellar Folds</td>
<td>73</td>
<td><strong>2.15</strong></td>
<td>1.19</td>
<td>0.14</td>
<td>57.00</td>
<td>83</td>
<td><strong>3.45</strong></td>
<td>1.34</td>
<td>0.15</td>
<td>97.41</td>
</tr>
<tr class="even">
<td>Nasolabial Folds</td>
<td>97</td>
<td><strong>2.03</strong></td>
<td>0.95</td>
<td>0.10</td>
<td>68.96</td>
<td>99</td>
<td><strong>3.50</strong></td>
<td>1.33</td>
<td>0.13</td>
<td>127.44</td>
</tr>
<tr class="odd">
<td>Upper Lip Lines</td>
<td>59</td>
<td><strong>2.16</strong></td>
<td>1.13</td>
<td>0.15</td>
<td>39.42</td>
<td>57</td>
<td><strong>3.91</strong></td>
<td>1.25</td>
<td>0.17</td>
<td>78.25</td>
</tr>
<tr class="even">
<td>Mouth Corners</td>
<td>74</td>
<td><strong>2.32</strong></td>
<td>1.04</td>
<td>0.12</td>
<td>50.82</td>
<td>84</td>
<td><strong>3.98</strong></td>
<td>1.18</td>
<td>0.13</td>
<td>104.77</td>
</tr>
</tbody>
</table>

![](media/image2.wmf)

### 12-month Efficacy Data

> Although the study design did not afford a controlled comparison at
> twelve months, the Artecoll efficacy (improvement over pre-treatment
> values) at twelve months was compared to the Control group efficacy at
> six months. Non-parametric Mann-Whitney U tests were utilized for
> these comparisons. The results for masked observer FFA scale ratings
> are summarized in Table 10. The Nasolabial fold area showed
> significantly greater improvement for Artecoll at twelve months than
> for Control at six months. No differences were significant for the
> other treatment areas. These results concur with the comparison of the
> treatments at six months.

Table 10.

Comparison of improvement in masked observer FFA Scale ratings twelve
months following Artecoll treatment with improvement six months
following Control treatment

  ------------- ------------- ------- ------- ------ ------------- ------- ------- ------- -------- --------
  Treatment     Artecoll                             Control                               U        p
  Area          12-Month                             6-Month                                        
                Improvement                          Improvement                                    

                N             Mean    Std.    Std.   N             Mean    Std.    Std.             
                                      Dev.    Err.                         Dev.    Err.             

  Glabellar     59            0.27    0.85    0.11   79            0.32    0.68    0.08    2303     .906
  Folds                                                                                             

  Nasolabial    79            0.98    0.93    0.10   91            -0.00   0.90    0.09    1459     \<.001
  Folds                                                                                             

  Upper Lip     46            0.19    0.71    0.10   50            0.22    0.48    0.07    1070.5   .559
  Lines                                                                                             

  Mouth Corners 58            -0.01   0.87    0.11   79            0.09    0.74    0.08    2078     .353
  ------------- ------------- ------- ------- ------ ------------- ------- ------- ------- -------- --------

> Investigator FFA Scale ratings were used for similar comparisons.
> Improvement in the Artecoll group after twelve months was
> significantly greater than improvement in the established Control
> group after six months for all fold sites, as summarized in Table 11.

Table 11.

Comparison of improvement in investigator FFA Scale ratings twelve
months following Artecoll treatment with improvement six months
following Control treatment

  ------------- ------------- ------ ------- ------ ------------- ------ ------- ------- ------- --------
  Treatment     Artecoll                            Control                              U       p
  Area          12-Month                            6-Month                                      
                Improvement                         Improvement                                  

                N             Mean   Std.    Std.   N             Mean   Std.    Std.            
                                     Dev.    Err.                        Dev.    Err.            

  Glabellar     69            1.29   1.01    0.12   82            0.46   1.04    0.12    1505    \<.001
  Folds                                                                                          

  Nasolabial    91            2.07   1.06    0.11   96            0.01   0.86    0.09    566.5   \<.001
  Folds                                                                                          

  Upper Lip     58            1.41   1.02    0.13   54            0.05   0.98    0.13    507.5   \<.001
  Lines                                                                                          

  Mouth Corners 72            1.51   1.23    1.14   80            0.02   0.83    0.09    766.5   \<.001
  ------------- ------------- ------ ------- ------ ------------- ------ ------- ------- ------- --------

> Investigator success ratings and subject satisfaction ratings for the
> Artecoll group at twelve months were compared to the ratings for the
> Control group at six months. Lower means indicate greater success in
> investigator ratings and greater satisfaction in patient ratings. The
> results are summarized in Tables 12 and 13. For all fold sites,
> investigators rated the Artecoll treatment at twelve months as
> significantly more successful than the control treatment at six
> months. Likewise, patients ratings indicated greater satisfaction with
> the Artecoll treatment at twelve months than with the Control
> treatment at six months.

Table 12.

Comparison of investigator success ratings twelve months following
Artecoll treatment with success ratings six months following Control
treatment

  ------------- ----------- ------ ------- ------ ---------- ------ ------- ------- -------- --------
  Treatment     Artecoll                          Control                           U        p
  Area          12-Months                         6-Months                                   

                N           Mean   Std.    Std.   N          Mean   Std.    Std.             
                                   Dev.    Err.                     Dev.    Err.             

  Glabellar     70          2.03   1.13    0.13   82         3.43   1.51    0.17    1403.5   \<.001
  Folds                                                                                      

  Nasolabial    92          1.64   0.74    0.08   96         4.05   1.32    0.13    853      \<.001
  Folds                                                                                      

  Upper Lip     58          2.15   0.98    0.13   54         4.13   1.28    0.17    449      \<.001
  Lines                                                                                      

  Mouth Corners 73          2.08   1.01    0.12   81         4.09   1.32    0.15    842.5    \<.001
  ------------- ----------- ------ ------- ------ ---------- ------ ------- ------- -------- --------

Table 13.

Comparison of subject satisfaction ratings twelve months following
Artecoll treatment with satisfaction six months following Control
treatment

  ------------- ----------- ------ ------- ------ ---------- ------ ------- ------- -------- --------
  Treatment     Artecoll                          Control                           U        p
  Area          12-Months                         6-Months                                   

                N           Mean   Std.    Std.   N          Mean   Std.    Std.             
                                   Dev.    Err.                     Dev.    Err.             

  Glabellar     70          2.11   1.14    0.14   82         3.44   1.35    0.15    1346.5   \<.001
  Folds                                                                                      

  Nasolabial    92          2.00   1.08    0.11   96         3.52   1.37    0.14    1813.5   \<.001
  Folds                                                                                      

  Upper Lip     58          2.17   1.12    0.15   54         3.94   1.28    0.17    516      \<.001
  Lines                                                                                      

  Mouth Corners 73          2.25   1.15    0.13   81         3.97   1.19    0.13    967.5    \<.001
  ------------- ----------- ------ ------- ------ ---------- ------ ------- ------- -------- --------

### Device failures and replacements

> One device failure, defined as an adverse event requiring removal of
> the implant was recorded for Artecoll in the controlled, randomized
> trial. Two such events were recorded for Control implant in the
> controlled, randomized trial.

## Open Label Trial

### Study design

> The study was an open label multi-center clinical trial conducted
> under conditional IDE approval. No Control group was included. 157
> subjects were treated and 1-year safety information was obtained for
> 126 subjects. Results are shown in Table 2, above.

### Device failures and replacements

> Two device failures, defined as an adverse event requiring removal of
> the implant were recorded for Artecoll in the open label trial.

## Additional Studies

> Two previous clinical studies on effectiveness and adverse events had
> been conducted in Frankfurt, Germany and published in 1995 (5) and
> 1998 (6). In the first prospective study, 118 subjects with 200
> implantation sites were followed for up to two years and the results
> evaluated clinically and with the help of an anonymous questionnaire.
> Overall, 89.5 % of the subjects were pleased or satisfied with the
> result; 10.5 % did not see a difference or had experienced a side
> effect.
>
> The second clinical study contained the evaluation of 515
> questionnaires sent out to patients 2 years after the implantation of
> Artecoll. Satisfaction with the treatment was rated "very good" in
> 29%, "good" in 38%, "satisfactory" in 23%, and "no difference" in 8%
> of the patients. The question, "would you repeat the treatment again?"
> was answered by 91% of the patients with "yes". The overall
> complication rate was 3%.

# Conclusions Drawn from the Studies

## Risk/benefit analysis

> The risk of treatment with Artecoll, as defined by number of adverse
> events, has been shown to be equivalent to or less than that of
> currently marketed Control implants. The benefit of treatment with
> Artecoll, as defined by degree of improvement, has been shown to be
> equivalent to or better than Control implants. Therefore, the
> risk/benefit ratio for Artecoll is equivalent to or better than that
> of the established Control implants.

## Safety

> The number of adverse events was lower for the Artecoll group than for
> the Control group. Additionally, the number of adverse events
> classified as severe was also lower. When comparing total number of
> subject with adverse events, there was no significant difference in
> adverse events rates between Artecoll and the Control. The
> pre-clinical and clinical data provide a reasonable assurance that
> Artecoll is safe when used in accordance with labeling.

## Effectiveness

> Artecoll has been shown to provide statistically better improvement
> than Control when used for the correction of Nasolabial Folds.
> Artecoll has also been shown to provide improvement that is not
> significantly different than that provided by the Control implants
> when used for the correction of Glabellar Folds, Upper Lip Lines, and
> Mouth Corners. Improvement in investigator FFA Scale ratings with
> Artecoll treatment was superior to Control treatment for all treatment
> areas. Investigator success ratings and subject satisfaction ratings
> for Artecoll treatment were superior to Control treatment for all
> treatment areas. Analyses of potential confounds and other factors
> were supportive of study validity.

The overall conclusion from the studies is that Artecoll is a safe
treatment that is equivalent to or better than the established Control
treatment in efficacy.

# References

1.  Carruthers A. Artecoll - an injectable micro-implant for longlasting
    soft tissue augmentation. Skin Therapy Letter 4 1999;(2):1.

2.  Morhenn V, Lemperle G, Gallo R. Phagocytosis of different
    particulate dermal filler substances by human macrophages and skin
    cells. To Be Published in Dermatol Surg 2002;28.

3.  Lemperle G, Ott H, Charrier U, Hecker J, Lemperle M. PMMA
    microspheres for intradermal implantation: Part I. Animal research.
    Ann Plast Surg 1991 Jan;26(1):57-63.

4.  Lemperle G, Morhenn V, Pestonjamasp V, Gallo R. Histology and
    migration studies of different injectable filler substances for soft
    tissue augmentation. Submitted to Plast Reconstr Surg 2002;110.

5.  Lemperle G, Hazan-Gauthier N, Lemperle M. PMMA microspheres
    (Artecoll) for skin and soft-tissue augmentation. Part II: Clinical
    investigations. Plast Reconstr Surg 1995 Sep;96(3):627-34.

6.  Lemperle G, Gauthier-Hazan N, Lemperle M. PMMA-Microspheres
    (Artecoll) for long-lasting correction of wrinkles: refinements and
    statistical results. Aesthetic Plast Surg 1998 Sep-1998 Oct
    31;22(5):356-65.

# Panel Recommendations (To be completed by FDA)

# CDRH Decision (To be completed by FDA)

# Approval Specifications (To be completed by FDA)