# Executive Clinical Summary

**P020012**

**Artecoll**

**Artes Medical, Inc.**

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

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

**TABLE OF CONTENTS**

[PART I]{.underline}

Product
Description..................................................................................2

Proposed Intended
Use..............................................................................2

[PART II]{.underline}

Artes Medical Clinical
Study........................................................................2

Artes Medical Study
Conduct.......................................................................7

Artes Medical Study
Results.......................................................................10

Study Objectives versus Study Results
..........................................................15

[PART III]{.underline}

Rofil Medical Clinical
Study......................................................................17

Rofil Medical Study Conduct
.....................................................................18

Rofil Medical Study
Results.......................................................................19

[PART IV]{.underline}

Bovine Collagen Immunogenicity
Study.........................................................20

Study Conduct
.......................................................................................23

Study
Results........................................................................................24

Study Objectives versus Study
Results...........................................................26

######## PART V .............................................................................................26

FFA Scale reference
photographs............................................Volume 3 p.
12-096

Attachment 2a (Duration of Adverse Events -- Artecoll treated patients)

Attachment 2b (Duration of Adverse Events -- Control group)

Attachment 2c (Duration of Adverse Events -- Rofil Study)

Attachment 2d (Duration of Adverse Events -- Bovine collagen
immunogenicity study)

###### PART I

## Product Description

Artecoll is a suspension of polymethylmethacrylate (PMMA) microspheres
in a 3.5% collagen solution.

> No changes were made in the final product composition or formulation
> between or during the Rofil and Artes Medical studies that are
> described below.

#### Proposed Indications for Use

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

**[PART II]{.underline}**

## I. Artes Medical Clinical Study {#i.-artes-medical-clinical-study .unnumbered}

a.  Design

    -   Prospective, randomized, double-blind, controlled clinical trial

    -   Compares Artecoll to Zyplast^®^ Implant for correction of:

        1.  Nasolabial Folds

        2.  Radial Upper Lip Lines

        3.  Depressed Mouth Corners

    -   Compares Artecoll to Zyderm^®^ Implant for correction of
        Glabellar Folds

b.  Inclusion/Exclusion Criteria

+----------------------------------+-----------------------------------+
| ### Inclusion                    | **[Exclusion]{.underline}**       |
+----------------------------------+-----------------------------------+
| -   Subjects 18 years of age or  | -   Subjects who were pregnant    |
|     older, of either sex         |                                   |
|                                  | -   Subjects who had been treated |
| -   Subjects having realistic    |     with collagen, Botulinum      |
|     expectations of the benefit  |     toxin, or other wrinkle/fold  |
|     and limitation of the        |     therapies within the last six |
|     augmentation procedure, as   |     months at any intended        |
|     determined by a willingness  |     implant area                  |
|     to sign the informed consent |                                   |
|     form after it has been       | -   Subjects considering          |
|     carefully explained. The     |     additional cosmetic           |
|     informed consent form        |     treatments to the treatment   |
|     includes the statement that  |     area at any later time during |
|     the subjects will not look   |     the study                     |
|     younger after the treatment, |                                   |
|     and that treatment with      | -   Subjects who had received     |
|     Artecoll does not replace a  |     chemotherapy agents or        |
|     facelift or eyelid surgery,  |     corticosteroids within the    |
|     nor does it replace the      |     last 3 months                 |
|     effect of laser treatment,   |                                   |
|     chemical peel or             | -   Subjects receiving UV light   |
|     dermabrasion on fine         |     therapy                       |
|     wrinkling.                   |                                   |
|                                  | -   Subjects who were planning to |
| -   Subjects able and willing to |     use substances which reduce   |
|     give informed consent        |     coagulation, such as aspirin, |
|                                  |     non-steroidal                 |
| -   Subjects presenting for      |     anti-inflammatory drugs or    |
|     correction of any of the     |     Coumadin, within the 4 weeks  |
|     following four types of      |     preceding treatment (this was |
|     dermal contour deformities   |     changed to 72 hours as of     |
|     of the face: - Glabellar     |     January 10^th^, 2000 per      |
|     Folds (right and/or left     |     Protocol Revision 1)          |
|     side and/or center)          |                                   |
|                                  | -   Subjects presenting with      |
|     -   Nasolabial Folds (right  |     history of autoimmune         |
|         and/or left side)        |     disorder                      |
|                                  |                                   |
|     -   Radial Upper Lip Lines   | -   Subjects presenting with      |
|         (right and/or left side) |     atrophic skin diseases at any |
|                                  |     intended treatment area       |
|     -   Depressed Corners of the |                                   |
|         Mouth (right and/or left | -   Subjects with very thin and   |
|         side)                    |     flaccid skin at any intended  |
|                                  |     treatment area                |
| -   Subjects willing and able to |                                   |
|     comply with the requirements | -   Subjects with known           |
|     of the study (e.g. study     |     susceptibility to keloids     |
|     duration, number of visits,  |                                   |
|     completion of                | -   Subjects with known lidocaine |
|     questionnaires)              |     hypersensitivity              |
|                                  |                                   |
|                                  | -   Subjects with dietary beef    |
|                                  |     allergy, or undergoing or     |
|                                  |     planning to undergo           |
|                                  |     desensitization to meat       |
|                                  |     products                      |
|                                  |                                   |
|                                  | -   Subjects with known allergy   |
|                                  |     to collagen                   |
|                                  |                                   |
|                                  | -   Subjects with severe          |
|                                  |     allergies manifested by a     |
|                                  |     history of anaphylaxis or     |
|                                  |     history or presence of        |
|                                  |     multiple severe allergies     |
|                                  |                                   |
|                                  | -   Subjects with cellulitis or   |
|                                  |     infection at the treatment    |
|                                  |     area                          |
|                                  |                                   |
|                                  | -   Subjects demonstrating        |
|                                  |     anti-bovine collagen serum    |
|                                  |     IgG levels outside the normal |
|                                  |     range at baseline (after      |
|                                  |     randomization)                |
|                                  |                                   |
|                                  | -   Subjects demonstrating a      |
|                                  |     positive skin test or two     |
|                                  |     equivocal skin tests (after   |
|                                  |     randomization)                |
+----------------------------------+-----------------------------------+

a.  Treatment Protocol

> 1\. Patient screened

2.  Patients randomized to receive either Artecoll or Zyplast/Zyderm
    treatment in one or more of the eight treatment areas (four for each
    side). Subjects were masked regarding the randomization assignment.

3.  Blood was then drawn for a test of serum IgG level and the subject
    received the collagen skin test that correlated with the
    randomization assignment

4.  Subject underwent a 30-day observation period following the collagen
    skin test.

5.  In the case of equivocal test results, the subject underwent a
    second skin test with a subsequent 30-day observation period.

6.  Upon a negative skin test and a serum IgG level within normal range,
    the subject received treatment with Artecoll or Zyplast/Zyderm
    according to the randomization assignment.

    i.  Among subjects treated with the Control, Zyplast was used for
        Nasolabial folds, Upper lip lines and Mouth Corners

    ii. Zyderm was used for Glabellar Folds on the basis of labeling for
        Zyderm/Zyplast.

7.  Before treatment, a topical or deep dermal anesthetic was applied to
    areas selected for treatment as necessary.

8.  During each treatment session, the appropriate implant was injected
    deep dermally, immediately above the subcutaneous tissue, using a
    tunneling technique.

9.  To even distribution, the implant was spread and modeled with the
    fingertips.

10. Post-procedure, subjects were encouraged to minimize facial movement
    for several days following the treatment session.

11. The treatment course lasted up to one month and included a total of
    up to 3 treatment sessions.

    a.  Follow-up Protocol

> 1\. Follow-up intervals

-   All subjects in both treatment groups were scheduled to follow-up at
    1, 3, and 6 months post-treatment.

-   Only the Artecoll treatment group patients were seen again at 12
    months post-treatment to assess the occurrence of late adverse
    events

2.  Follow-up Assessments included

    -   Adverse event assessment, documentation and additional
        treatments required

    -   Photographic documentation using a standardized process

3.  Assessment Tools

+------------+---------------------------+----------------------------+
| **         | **Assessment Tool**       | **Details Regarding        |
| Assessment |                           | Assessment Tool**          |
| made by:** |                           |                            |
+------------+---------------------------+----------------------------+
| Masked     | Facial Fold Assessment    | A scale created and        |
| Observer   | (FFA) Scale               | validated for this study   |
|            |                           | for:                       |
|            | (Validated Scale)         |                            |
|            |                           | -   Glabellar Folds        |
|            |                           |                            |
|            |                           | -   Nasolabial Folds       |
|            |                           |                            |
|            |                           | -   Radial Upper Lip Lines |
|            |                           |                            |
|            |                           | -   Marionette Lines       |
|            |                           |                            |
|            |                           | And not for mouth corners. |
|            |                           |                            |
|            |                           | Each fold/line is graded   |
|            |                           | on a 0 -- 5 point scale    |
|            |                           | based on reference photos  |
|            |                           | where 0 is considered the  |
|            |                           | least severe, optimal      |
|            |                           | condition.                 |
|            |                           |                            |
|            |                           | \_\_\_                     |
|            |                           | \_\_\_\_\_\_\_\_\_\_\_\_\_ |
|            |                           | \_\_\_\_\_\_\_\_\_\_\_\_\_ |
|            |                           |                            |
|            |                           | Reference photographs used |
|            |                           | by the masked observers    |
|            |                           | were the same size as the  |
|            |                           | photographs being          |
|            |                           | evaluated. (Reference      |
|            |                           | photographs appear in      |
|            |                           | Volume 3 p. 12-096)        |
|            |                           |                            |
|            |                           | \_\_\_                     |
|            |                           | \_\_\_\_\_\_\_\_\_\_\_\_\_ |
|            |                           | \_\_\_\_\_\_\_\_\_\_\_\_\_ |
|            |                           |                            |
|            |                           | Although the scale was not |
|            |                           | validated for this,        |
|            |                           | non-integral values for    |
|            |                           | Masked Observer FFA scale  |
|            |                           | ratings occurred under 2   |
|            |                           | circumstances:             |
|            |                           |                            |
|            |                           | 1)  For any facial         |
|            |                           |     location at any time   |
|            |                           |     point ratings were     |
|            |                           |     averaged across raters |
|            |                           |     and sides              |
|            |                           |                            |
|            |                           | 2)  MO used ½ point steps  |
|            |                           |     for FFA ratings        |
|            |                           |     between 2 FFA scale    |
|            |                           |     anchor points          |
|            |                           |                            |
|            |                           | Then the pre-treatment     |
|            |                           | severity was determined by |
|            |                           | rounding the FFA scale     |
|            |                           | score to the nearest       |
|            |                           | integer.                   |
|            |                           |                            |
|            |                           | \_\_\_                     |
|            |                           | \_\_\_\_\_\_\_\_\_\_\_\_\_ |
|            |                           | \_\_\_\_\_\_\_\_\_\_\_\_\_ |
|            |                           |                            |
|            |                           | Interclass correlations    |
|            |                           | for rater reliability of   |
|            |                           | masked observer FFA        |
|            |                           | ratings were acceptable    |
|            |                           | being greater than 0.8 for |
|            |                           | each treatment area.       |
+------------+---------------------------+----------------------------+
| Unblinded  | Rating of Treatment       | 1\) During each follow-up  |
| In         | Success                   | visit, the unblinded       |
| vestigator |                           | investigator rated the     |
|            | *(Scale not validated)*   | success of the implant at  |
|            |                           | each treatment area using  |
|            |                           | the following five point   |
|            |                           | rating scale. These        |
|            |                           | evaluations were based on  |
|            |                           | seeing the patient in      |
|            |                           | person.                    |
|            |                           |                            |
|            |                           | > 1 = Completely           |
|            |                           | > Successful (Defined as   |
|            |                           | > Optimal Desired Outcome) |
|            |                           | >                          |
|            |                           | > 2 = Very Successful      |
|            |                           | >                          |
|            |                           | > 3 = Moderately           |
|            |                           | > Successful               |
|            |                           | >                          |
|            |                           | > 4 = Somewhat Successful  |
|            |                           | >                          |
|            |                           | > 5 = Not at all           |
|            |                           | > Successful               |
|            |                           |                            |
|            |                           | 2\) During each follow-up  |
|            |                           | visit, the unblinded       |
|            |                           | investigator rated the     |
|            |                           | success of the implant     |
|            |                           | based on seeing the        |
|            |                           | patient in person and      |
|            |                           | using reduced size FFA     |
|            |                           | reference photographs.     |
+------------+---------------------------+----------------------------+
| Blinded    | Subject satisfaction of   | During each follow-up      |
| Patient    | treatment                 | visit, subject             |
|            |                           | satisfaction with the      |
|            | *(Scale Not Validated)*   | result of each treatment   |
|            |                           | area was assessed using a  |
|            |                           | questionnaire at each      |
|            |                           | follow-up period. Subjects |
|            |                           | rated their personal       |
|            |                           | opinion of each treatment  |
|            |                           | area using the following   |
|            |                           | 5-point rating scale:      |
|            |                           |                            |
|            |                           | 1 = Very Satisfied         |
|            |                           |                            |
|            |                           | > 2 = Satisfied            |
|            |                           |                            |
|            |                           | 3 = Somewhat Satisfied     |
|            |                           |                            |
|            |                           | > 4 = Dissatisfied         |
|            |                           | >                          |
|            |                           | > 5 = Very Dissatisfied    |
+------------+---------------------------+----------------------------+

a.  Study Endpoints

    1.  Primary Endpoints

        -   [Objective 1]{.underline}: The cosmetic correction will be
            assessed using the FFA Scale, related to the Fitzpatrick
            scale, but adapted to the deep folds that are the subject of
            this study, rather than the fine wrinkles for which the
            Fitzpatrick scale was developed. A comparison will be made
            between Artecoll and Zyplast/Zyderm by measuring the
            correction that remains at the evaluation 6 months after
            completion of the treatment course. The null hypothesis will
            be that there is no difference between Artecoll and
            Zyplast/Zyderm 6 months after completion of the treatment
            course. A clinically significant difference will be defined
            as a difference of at least one FFA Scale classification.

        -   [Objective 2:]{.underline} The assessment of safety will be
            based on the incidence of serious unanticipated adverse
            events. Unanticipated adverse events will be characterized
            by the severity and relation to the implant product.

> In addition, the occurrence of all anticipated adverse events will be
> assessed at each follow-up period and compared between treatment
> groups.
>
> The level of serum IgG will be monitored pre-treatment and at 1 month
> post-treatment. If the IgG level is elevated at the 1 month
> post-treatment visit, an additional sample will be taken at the 3
> month visit. If the 3 month sample is elevated, a final sample will be
> taken at the 6 month post-treatment visit. The occurrence of levels
> falling outside the normal range will be compared between treatment
> groups.

#### Secondary Endpoints

-   [Objective 3:]{.underline} The quality of the initial treatment
    result will be characterized using the FFA Scale and will be used to
    characterize the cosmetic correction during the early period up to 3
    months post-treatment. The percent of folds/lines that exhibit a
    decrease of at least one classification (improvement) between the
    pre-implant assessment and the 1 and 3 month post-treatment
    assessments will be calculated for each treatment group.

-   [Objective 4:]{.underline} The physician's assessment of success
    will be characterized using a non-parametric 5-point scale, measured
    at 1, 3, and 6 months post-treatment.

-   [Objective 5:]{.underline} The patient's assessment of satisfaction
    will be characterized using a non-parametric 5-point scale, measured
    at 1, 3, and 6 months post-treatment.

#### II. Artes Medical Study Conduct {#ii.-artes-medical-study-conduct .unnumbered}

> a\. Enrollment

1\. Included 285 subjects (141 Artecoll, 144 Control)

> 2\. 111 subjects being available for 1-year safety evaluation
>
> b\. Demographics

+-------------------------+---------------+-----------------+----------+
|                         | **Artecoll**  | **Control**     | **p      |
|                         |               |                 | -value** |
+-------------------------+---------------+-----------------+----------+
| Gender                  |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### M                  | 11 (8.6%)     | 11 (8.9%)       | 1.000    |
| ale {#male .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### Femal              | 117 (91.4%)   | 112 (91.1%)     |          |
| e {#female .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| Mean Age (Std. dev.)    | 53.2 (10.3)   | 51.2 (11.3)     | 0.157    |
+-------------------------+---------------+-----------------+----------+
| Ethnicity               |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### Caucasian {        | 102(76.7%)    | 107 (82.3%)     | 0.277    |
| #caucasian .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### Hispanic           | 24 (18.0%)    | 21 (16.2%)      |          |
| {#hispanic .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### Asi                | 1 (0.8%)      | 1 (0.8%)        |          |
| an {#asian .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### Oth                | 6 (4.5%)      | 1 (0.8%)        |          |
| er {#other .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| Smoking Rate            |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| -   None                | 122 (91.0%)   | 108 (83.1%)     | 0.061    |
+-------------------------+---------------+-----------------+----------+
| -   Low                 | 8 (6.0%)      | 18 (13.8%)      |          |
+-------------------------+---------------+-----------------+----------+
| -   Medium              | 4 (3.0%)      | 3 (2.3%)        |          |
+-------------------------+---------------+-----------------+----------+
| -   High                | 0 (0.0%)      | 1 (0.8%)        |          |
+-------------------------+---------------+-----------------+----------+
| Sun Exposure            |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| -   Low                 | 69 (51.9%)    | 84 (64.6%)      | *        |
|                         |               |                 | *0.043** |
+-------------------------+---------------+-----------------+----------+
| -   Medium              | 49 (36.8%)    | 35 (26.9%)      |          |
+-------------------------+---------------+-----------------+----------+
| -   High                | 15 (11.3%)    | 11 (8.5%)       |          |
+-------------------------+---------------+-----------------+----------+
| Mean pretreatment       |               |                 |          |
| masked observer FFA     |               |                 |          |
| Scale Ratings (Std.     |               |                 |          |
| dev.)                   |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| ####                    | 1.42 (0.90)   | 1.40 (0.86)     | 0.934    |
| Glabellar Folds {#glabe |               |                 |          |
| llar-folds .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #### Na                 | **1.74        | **1.45 (1.02)** | *        |
| solabial Folds {#nasola | (1.06)**      |                 | *0.039** |
| bial-folds .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| ####                    | 1.17 (0.82)   | 1.18 (0.86)     | 0.886    |
| Upper Lip Lines {#upper |               |                 |          |
| -lip-lines .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+
| #                       | 1.91 (1.15)   | 1.87 (1.10)     | 0.891    |
| ### Mouth Corners {#mou |               |                 |          |
| th-corners .unnumbered} |               |                 |          |
+-------------------------+---------------+-----------------+----------+

> *Using the Spearman Rank Order Correlation, the sponsor determined
> that the smoking rates were not associated with treatment effects and
> thus not a source of bias in the clinical trial.*
>
> *Using the Spearman Rank Order Correlation, the sponsor found only one
> correlation significant for sun exposure. In the Control group,
> Nasolabial fold improvement was found to be negatively correlated with
> sun exposure. Lower sun exposure was associated with greater
> improvement in this group.*
>
> *Please note that the mean pretreatment masked observer FFA scale
> ratings for nasolabial folds indicate that the fold severity is more
> severe for the Artecoll treatment group versus the control group
> severity. This statistically significant difference between groups
> allows the Artecoll treatment group more room for improvement than the
> control.*

+----------------------+-----------+------------+---------------------+
|                      | **A       | *          | **p-value**         |
|                      | rtecoll** | *Control** |                     |
+----------------------+-----------+------------+---------------------+
| Treated folds        |           |            |                     |
| (treated subjects)   |           |            |                     |
+----------------------+-----------+------------+---------------------+
| Glabellar Folds      | 155 (81)  | 165 (86)   | 0.153 (0.327)       |
+----------------------+-----------+------------+---------------------+
| Nasolabial Folds     | 214 (108) | 206 (104)  | 0.939 (1.00)        |
+----------------------+-----------+------------+---------------------+
| Upper lip lines      | 137 (69)  | 116 (59)   | 0.182 (0.415)       |
+----------------------+-----------+------------+---------------------+
| Mouth corners        | 86        | 87         | 0.210 (0.638)       |
+----------------------+-----------+------------+---------------------+
| Number of facial     |           |            |                     |
| fold areas treated   |           |            |                     |
+----------------------+-----------+------------+---------------------+
| > 1 area             | 20        | 22         | 0.412               |
+----------------------+-----------+------------+---------------------+
| > 2 areas            | 36        | 24         |                     |
+----------------------+-----------+------------+---------------------+
| > 3 areas            | 36        | 42         |                     |
+----------------------+-----------+------------+---------------------+
| > 4 areas            | 36        | 35         |                     |
+----------------------+-----------+------------+---------------------+
| Bilateral treatment  |           |            |                     |
| to:                  |           |            |                     |
+----------------------+-----------+------------+---------------------+
| > Glabellar Folds    | 74        | 79         | 0.312               |
+----------------------+-----------+------------+---------------------+
| > Nasolabial Folds   | 106       | 102        | 0.886               |
+----------------------+-----------+------------+---------------------+
| > Upper Lip Lines    | 68        | 57         | 0.621               |
+----------------------+-----------+------------+---------------------+
| > Mouth Corners      | 85        | 83         | 0.963               |
+----------------------+-----------+------------+---------------------+
| Unilateral treatment |           |            |                     |
| to:                  |           |            |                     |
+----------------------+-----------+------------+---------------------+
| > Glabellar Folds    | 7         | 7          | 0.578               |
+----------------------+-----------+------------+---------------------+
| > Nasolabial Folds   | 2         | 2          | 0.674               |
+----------------------+-----------+------------+---------------------+
| > Upper Lip Lines    | 1         | 2          | 0.485               |
+----------------------+-----------+------------+---------------------+
| > Mouth Corners      | 1         | 4          | 0.173               |
+----------------------+-----------+------------+---------------------+

> c\. Accountability

+---------------+--------+--------+--------+--------+--------+--------+
| Patient       |        |        |        |        |        |        |
| Accounting -  |        |        |        |        |        |        |
| Artes medical |        |        |        |        |        |        |
| study --      |        |        |        |        |        |        |
| Artecoll      |        |        |        |        |        |        |
| patients      |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
|               | Preop  | I      | 1      | 3      | 6      | 12     |
|               |        | ntraop | month  | months | months | months |
+---------------+--------+--------+--------+--------+--------+--------+
| ##### T       | 141    |        |        |        |        |        |
| heoretical^1^ |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Device        | 0      | 0      | 0      | 1      | 1      | 1      |
| removals,     |        |        |        | **\*** | **\*** | **\*** |
| (cumulative)  |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Expected^2^   | 141    | 141    | 141    | 140    | 140    | 140    |
+---------------+--------+--------+--------+--------+--------+--------+
| Lost to       | 0      | 0      | 2      | 4      | 6      | 10     |
| follow-up     |        |        |        |        |        |        |
| (cumulative)  |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Aborted study | 13     | 13     | 14     | 15     | 15     | 16     |
| (includes not |        |        |        |        |        |        |
| treated and   |        |        |        |        |        |        |
| voluntary     |        |        |        |        |        |        |
| withdrawal)   |        |        |        |        |        |        |
| (cumulative)  |        |        |        |        |        |        |
+---------------+--------+--------+--------+--------+--------+--------+
| Evaluated^3^  | 128    | 128    | 125    | 121    | 119    | 114    |
+---------------+--------+--------+--------+--------+--------+--------+
| \% Expected   | 100%   | 100%   | 100%   | 99.3%  | 99.3%  | 99.3%  |
| Follow-up     |        |        |        |        |        |        |
|               | 1      | 1      | 1      | 1      | 1      | 1      |
|               | 41/141 | 41/141 | 41/141 | 40/141 | 40/141 | 40/141 |
+---------------+--------+--------+--------+--------+--------+--------+
| #             | 90%    | 90%    | 89%    | 86%    | 85%    | 81%    |
| #### Actual % |        |        |        |        |        |        |
|  Follow-up^4^ | 1      | 1      | 1      | 1      | 1      | 1      |
|               | 28/141 | 28/141 | 25/141 | 21/140 | 19/140 | 14/140 |
+---------------+--------+--------+--------+--------+--------+--------+

**\*** Subject with device removal (due to lumpiness) was seen at all
follow-up visits

1.  Theoretical = Patients enrolled in the study

2.  Expected = Theoretical -- Device removals

3.  Evaluated = Theoretical -- (Failures+ Lost to Follow-Up + Aborted)

> 4 As per evaluated^3^

+------------------+-------+-----------+---------+---------+----------+
| Patient          |       |           |         |         |          |
| Accounting --    |       |           |         |         |          |
| Artes Medical    |       |           |         |         |          |
| Study - Control  |       |           |         |         |          |
| Patients         |       |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+
|                  | Preop | Intraop   | 1 month | 3       | 6 months |
|                  |       |           |         | months  |          |
+------------------+-------+-----------+---------+---------+----------+
| Theoretical^1^   | 144   |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+
| Device removals, | 0     | 0         | 0       | 0       | 0        |
| (cumulative)     |       |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+
| Expected^2^      | 144   | 144       | 144     | 144     | 144      |
+------------------+-------+-----------+---------+---------+----------+
| Lost to          | 0     | 0         | 0       | 2       | 2        |
| follow-up        |       |           |         |         |          |
| (cumulative)     |       |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+
| Aborted study    | 21    | 21        | 21      | 22      | 23       |
| (includes not    |       |           |         |         |          |
| treated and      |       |           |         |         |          |
| voluntary        |       |           |         |         |          |
| withdrawal)      |       |           |         |         |          |
| (cumulative)     |       |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+
| Evaluated^3^     | 123   | 123       | 123     | 120     | 119      |
+------------------+-------+-----------+---------+---------+----------+
| \% Expected      | 100%  | 100%      | 100%    | 100%    | 100%     |
| Follow-up        |       |           |         |         |          |
|                  | 14    | 144/144   | 144/144 | 144/144 | 144/144  |
|                  | 4/144 |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+
| ##### Actua      | 85%   | 85%       | 85%     | 83%     | 83%      |
| l % Follow-up^4^ |       |           |         |         |          |
|                  | 12    | 123/144   | 123/144 | 123/144 | 123/144  |
|                  | 3/144 |           |         |         |          |
+------------------+-------+-----------+---------+---------+----------+

1\. Theoretical = Patients enrolled in the study

2\. Expected = Theoretical -- Device removals

3\. Evaluated = Theoretical -- (Failures+ Lost to Follow-Up + Aborted)

4\. As per evaluated^3^

> d\. Adequacy of Blinding
>
> 1\) Patient Satisfaction
>
> 1 month -- guess rates were not different than chance
>
> 3 months -- guess rates were 61.3% (p = 0.001) accurate
>
> 6 months -- guess rates were 73.6% (p \< 0.001) accurate
>
> Additional analysis (table 57 p. 12-053) demonstrates that treatment
> guesses at 6 months were not related to outcome on the masked observer
> FFA scale ratings.
>
> 2\) Masked Observer - The observers were not asked questions regarding
> their guesses about treatment assignment or follow-up time for the
> photos. No conclusions can be drawn regarding the efficacy of the
> blinding of the masked observers.

#### Artes Medical Study Results

> *The sponsor has performed a number of post-hoc supplemental analyses
> of various subsets of patients. These subset analyses have not been
> included in this review memo as they do not provide any additional
> information that are not already addressed in the prospectively
> defined data analysis.*

a.  Safety

######### ^Onset\ of\ Adverse\ Events\ --\ Artecoll\ patients\ in\ the\ Artes\ Medical\ Study^ 

+------------+----------+--------+-------+-------+-------+----------+
|            | **24-48  | **1    | **1   | **3   | **6   | **12     |
|            | hours**  | week** | mo    | mon   | mon   | months** |
|            |          |        | nth** | ths** | ths** |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Number   | 128      | 128    | 112   | 106   | 113   | 111      |
| of         |          |        |       |       |       |          |
| patients   |          |        |       |       |       |          |
| e          |          |        |       |       |       |          |
| valuated** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Total    | 12       | 3      | 2     | 3     | 2     | 0        |
| number of  |          |        |       |       |       |          |
| patients   |          |        |       |       |       |          |
| with       |          |        |       |       |       |          |
| adverse    |          |        |       |       |       |          |
| events**   |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Total    | 14       | 4\*    | 2     | 4     | 2     | 0        |
| number of  |          |        |       |       |       |          |
| adverse    |          |        |       |       |       |          |
| events**   |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| *          | 3        | 0      | 0     | 3     | []{.  | [        |
| *Lumpiness |          |        |       |       | mark} | ]{.mark} |
| at         |          |        |       |       |       |          |
| injection  |          |        |       |       | 2     | 0        |
| area more  |          |        |       |       |       |          |
| than one   |          |        |       |       |       |          |
| month      |          |        |       |       |       |          |
| after      |          |        |       |       |       |          |
| i          |          |        |       |       |       |          |
| njection** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **         | 6        | 1\*    | 0     | 0     | 0     | 0        |
| Persistent |          |        |       |       |       |          |
| swelling   |          |        |       |       |       |          |
| or         |          |        |       |       |       |          |
| redness**  |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| *          | 2        | 0      | 2     | 0     | 0     | 0        |
| *Increased |          |        |       |       |       |          |
| sen        |          |        |       |       |       |          |
| sitivity** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Rash,    | 0        | 1      | 0     | 1     | 0     | 0        |
| itching    |          |        |       |       |       |          |
| more than  |          |        |       |       |       |          |
| 48 hours   |          |        |       |       |       |          |
| after      |          |        |       |       |       |          |
| i          |          |        |       |       |       |          |
| njection** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Blurred  | 0        | 1      | 0     | 0     | 0     | 0        |
| vision**   |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Flu-like | 0        | 1      | 0     | 0     | 0     | 0        |
| symptoms** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **         | 1        | 0      | 0     | 0     | 0     | 0        |
| Recurrence |          |        |       |       |       |          |
| of         |          |        |       |       |       |          |
| existing   |          |        |       |       |       |          |
| herpes     |          |        |       |       |       |          |
| labialis** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Sen      | 0        | 0      | 0     | 0     | 0     | 0        |
| sitization |          |        |       |       |       |          |
| reac       |          |        |       |       |       |          |
| tions^1^** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| *          | 0        | 0      | 0     | 0     | 0     | 0        |
| *Abscess** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **         | 0        | 0      | 0     | 0     | 0     | 0        |
| Visibility |          |        |       |       |       |          |
| of the     |          |        |       |       |       |          |
| puncture   |          |        |       |       |       |          |
| area**     |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| *          | 0        | 0      | 0     | 0     | 0     | 0        |
| *Granuloma |          |        |       |       |       |          |
| or         |          |        |       |       |       |          |
| e          |          |        |       |       |       |          |
| nlargement |          |        |       |       |       |          |
| of the     |          |        |       |       |       |          |
| implant**  |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **I        | 0        | 0      | 0     | 0     | 0     | 0        |
| nfection** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Other    | 1 --dry  | 0      | 0     | 0     | 0     | 0        |
| local      | skin     |        |       |       |       |          |
| compl      |          |        |       |       |       |          |
| ications** |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Other    | 1 --     | 0      | 0     | 0     | 0     | 0        |
| systemic   | v        |        |       |       |       |          |
| compl      | asovagal |        |       |       |       |          |
| ications** | episode, |        |       |       |       |          |
|            | patient  |        |       |       |       |          |
|            | briefly  |        |       |       |       |          |
|            | lost     |        |       |       |       |          |
|            | consc    |        |       |       |       |          |
|            | iousness |        |       |       |       |          |
|            | during   |        |       |       |       |          |
|            | i        |        |       |       |       |          |
|            | njection |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+
| **Severe   | 0        | 0      | 0     | 0     | 0     | 0        |
| illness,   |          |        |       |       |       |          |
| trauma,    |          |        |       |       |       |          |
| death**    |          |        |       |       |       |          |
+------------+----------+--------+-------+-------+-------+----------+

\* Subject reported that event occurred 3 additional times -- no dates
for onset of 2^nd^ and 4^th^ times

> 1\. As defined per each investigator.

Onset of Adverse Events -- Control subjects in the Artes Medical Study

  ----------------- -------------- ---------- ---------- ---------- ------------
                    **24-48        **1 week** **1        **3        **6 months**
                    hours**                   month**    months**   

  **Number of       123            123        111        109        116
  patients                                                          
  evaluated**                                                       

  **Total number of 10             1          3          2          4
  patients with                                                     
  adverse events**                                                  

  **Total number of 21             3          4          2          6
  adverse events**                                                  

  **Lumpiness at    2              0          1          0          1
  injection area                                                    
  more than one                                                     
  month after                                                       
  injection**                                                       

  **Persistent      9              1          1          2          0
  swelling or                                                       
  redness**                                                         

  **Increased       1              0          0          0          0
  sensitivity**                                                     

  **Rash, itching   1              1          0          0          0
  more than 48                                                      
  hours after                                                       
  injection**                                                       

  **Blurred         0              0          0          0          0
  vision**                                                          

  **Flu-like        0              0          0          0          1
  symptoms**                                                        

  **Recurrence of   0              0          0          0          0
  existing herpes                                                   
  labialis**                                                        

  **Sensitization   3              1          2          0          0
  reactions^1^**                                                    

  **Abscess**       2              0          0          0          1

  **Visibility of   2              0          0          0          0
  the puncture                                                      
  area**                                                            

  **Granuloma or    1              0          0          0          0
  enlargement of                                                    
  the implant**                                                     

  **Infection**     0              0          0          0          1

  **Other local     0              0          0          0          1 --acneform
  complications**                                                   

  **Other systemic  0              0          0          0          0
  complications**                                                   

  **Severe illness, 0              0          0          0          1 -
  trauma, death**                                                   carjacking
  ----------------- -------------- ---------- ---------- ---------- ------------

> 1\. As defined per each investigator.

Duration of Adverse Events:

> Please see Attachment 2a and 2b for the Duration of adverse events in
> Artecoll treated patients and Control group patients.

Summary of incidence of adverse events:

+-------------------------+--------------------+----------------------+
|                         | ##### Artecoll     | ##### Control        |
+-------------------------+--------------------+----------------------+
| **Number of adverse     | 26                 | 36                   |
| events**                |                    |                      |
+-------------------------+--------------------+----------------------+
| **Number of patients    | 21                 | 16                   |
| experiencing adverse    |                    |                      |
| events**                |                    |                      |
+-------------------------+--------------------+----------------------+
| **Total number of       | 128                | 123                  |
| subjects treated**      |                    |                      |
+-------------------------+--------------------+----------------------+
| **% of subjects with    | 16.4%              | 13.0%                |
| adverse events**        |                    |                      |
+-------------------------+--------------------+----------------------+

*The top 3 adverse events occurring in the Artecoll treatment group were
lumpiness more than 1 month post-injection, persistent swelling or
redness, and increased sensitivity.*

*For Artecoll treated patients, these events lasted over 3 months in*

-   *5/7 patients found to have lumpiness more than 1 month post
    injection*

-   *3/7 patients found to have persistent swelling or redness*

-   *¼ patients found to have increased sensitivity*

*For control treated patients, these events lasted over 3 months in:*

-   *2/4 patients found to have lumpiness more than 1 month post
    injection*

-   *9/12 patients found to have persistent swelling or redness*

-   *1/1 patient found to have increased sensitivity*

    a.  Effectiveness

**The results of the Masked Observer Assessments are shown in the
following table:**

+----------+--------------+----------+--------+---------+-----------+
| > **Fol  | >            | > **Tre  | **N**  | **Mean  | > **      |
| low-up** |  **Treatment | atment** |        | change  | P-Value** |
|          | > Area**     |          |        | in      |           |
|          |              |          |        | FFA**   |           |
+----------+--------------+----------+--------+---------+-----------+
| > **1    | > Glabellar  | >        | 64     | 0.17    | >         |
| -month** | > Folds      | Artecoll |        |         | **0.004** |
+----------+--------------+----------+--------+---------+-----------+
|          |              | > **C    | **77** | *       |           |
|          |              | ontrol** |        | *0.49** |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Nasolabial | >        | 91     | 0.75    | > 0.713   |
|          | > Folds      | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 91     | 0.74    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Upper Lip  | >        | 58     | 0.31    | > 0.205   |
|          | > Lines      | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 53     | 0.48    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Mouth      | >        | 71     | 0.46    | > 0.179   |
|          | > Corners    | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 76     | 0.30    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
| > **3-   | > Glabellar  | >        | 65     | 0.25    | > 0.348   |
| months** | > Folds      | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 75     | 0.35    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Nasolabial | > **Ar   | **87** | *       | > **      |
|          | > Folds      | tecoll** |        | *0.81** | \<0.001** |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 88     | 0.15    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Upper Lip  | >        | 53     | 0.18    | > 0.454   |
|          | > Lines      | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 51     | 0.25    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Mouth      | > **Ar   | **64** | *       | >         |
|          | > Corners    | tecoll** |        | *0.45** | **0.001** |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 77     | 0.01    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
| > **6-   | > Glabellar  | >        | 71     | 0.34    | > 0.971   |
| months** | > Folds      | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 79     | 0.32    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Nasolabial | > **Ar   | **92** | *       | > **      |
|          | > Folds      | tecoll** |        | *0.77** | \<0.001** |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 91     | 0.00    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Upper Lip  | >        | 55     | 0.08    | > 0.176   |
|          | > Lines      | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 50     | 0.22    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          | > Mouth      | >        | 69     | 0.26    | > 0.316   |
|          | > Corners    | Artecoll |        |         |           |
+----------+--------------+----------+--------+---------+-----------+
|          |              | >        | 79     | 0.09    |           |
|          |              |  Control |        |         |           |
+----------+--------------+----------+--------+---------+-----------+

The un-blinded investigator assessments of success (ranging from not at
all successful to completely successful; 1 -- 5 scale) are shown in the
following table:

+----------+--------------+----------+-------+--------+--------------+
| > **Fol  | >            | > **Tre  | >     | > **   | > **Standard |
| low-up** |  **Treatment | atment** | **N** | Mean** | >            |
|          | > Area**     |          |       |        |  Deviation** |
+----------+--------------+----------+-------+--------+--------------+
| >        | > Glabellar  | >        | > 68  | > 1.93 | > 0.94       |
|  1-month | > Folds      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 79  | > 1.91 | > 1.00       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Nasolabial | >        | > 93  | > 1.99 | > 0.89       |
|          | > Folds      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 93  | > 2.06 | > 1.03       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Upper Lip  | >        | > 61  | > 1.88 | > 0.82       |
|          | > Lines      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 54  | > 2.02 | > 0.88       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Mouth      | >        | > 74  | > 2.00 | > 0.97       |
|          | > Corners    | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 77  | > 2.55 | > 1.28       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
| >        | > Glabellar  | >        | > 67  | > 2.02 | > 1.00       |
| 3-months | > Folds      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 74  | > 2.68 | > 1.40       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Nasolabial | >        | > 89  | > 1.90 | > 0.87       |
|          | > Folds      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 89  | > 3.07 | > 1.41       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Upper Lip  | >        | > 58  | > 2.04 | > 0.90       |
|          | > Lines      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 51  | > 3.11 | > 1.39       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Mouth      | >        | > 68  | > 2.08 | > 0.94       |
|          | > Corners    | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 76  | > 3.38 | > 1.34       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
| >        | > Glabellar  | >        | > 74  | > 2.06 | > 1.07       |
| 6-months | > Folds      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 82  | > 3.43 | > 1.51       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Nasolabial | >        | > 97  | > 1.73 | > 0.69       |
|          | > Folds      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 96  | > 4.05 | > 1.32       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Upper Lip  | >        | > 60  | > 1.98 | > 0.93       |
|          | > Lines      | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 54  | > 4.13 | > 1.28       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          | > Mouth      | >        | > 73  | > 2.19 | > 0.98       |
|          | > Corners    | Artecoll |       |        |              |
+----------+--------------+----------+-------+--------+--------------+
|          |              | >        | > 81  | > 4.09 | > 1.32       |
|          |              |  Control |       |        |              |
+----------+--------------+----------+-------+--------+--------------+

> Patient Satisfaction

  ---------- ------------ ---------- -------- --------- --------- -------- ---------
  Time       Treatment    Artecoll                      Control            
  (months)   area                                                          

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

  1          Glabellar    66         1.86     0.97      78        1.94     0.94
             Folds                                                         

  1          Nasolabial   92         1.85     1.03      93        1.92     0.89
             Folds                                                         

  1          Upper Lip    61         1.94     1.09      54        1.98     1.04
             Lines                                                         

  1          Mouth        74         2.01     0.94      77        2.32     1.07
             Corners                                                       

  3          Glabellar    67         2.22     1.13      74        2.70     1.34
             Folds                                                         

  3          Nasolabial   89         2.16     1.08      89        2.78     1.30
             Folds                                                         

  3          Upper Lip    58         2.14     1.05      51        3.07     1.30
             Lines                                                         

  3          Mouth        68         2.29     1.08      77        3.06     1.29
             Corners                                                       

  6          Glabellar    74         2.14     1.19      82        3.44     1.35
             Folds                                                         

  6          Nasolabial   97         2.02     0.95      96        3.52     1.37
             Folds                                                         

  6          Upper Lip    60         2.17     1.12      54        3.94     1.28
             Lines                                                         

  6          Mouth        73         2.31     1.04      81        3.97     1.19
             Corners                                                       
  ---------- ------------ ---------- -------- --------- --------- -------- ---------

> *Both the unmasked investigator assessment of patient success and the
> blinded patient satisfaction rating demonstrated higher success in the
> Artecoll treated group versus the control. However, the potential for
> bias is present as the investigator was not blinded to treatment group
> and the assessment of patient blinding demonstrated that over 73.6% of
> patients accurately guessed their randomization assignment at 6
> months.*

**IV. Did the Study Meet Its Objectives?**

[Objective 1]{.underline} (a primary objective) was to explore whether
the cosmetic correction provided by Artecoll at the end of a six-month
period following injection is superior to that provided by
Zyplast/Zyderm at the same time period.

*Although a statistically significant difference was noted at six months
for patients in the Artecoll treatment arm versus the control in the
area of the NL fold, it is unknown whether this represents a clinically
detectable difference as the FFA scale only recognizes full point
differences. The findings may be skewed by the statistically significant
difference of the pre-treatment severity score with the Artecoll group
that was greater (more severe at baseline) than the control group. The
sponsor states that this issue was addressed by using a non-parametric
Mann-Whitney U tests for these comparisons since the severity ratings
were positively skewed. The ability of this test to adequately
compensate for this difference should be considered.*

*The results show that Artecoll efficacy in other 3 treatment areas
versus the control has not been demonstrated as per objective 1.*

The sponsor states that Artecoll efficacy from the perspective of the
unblinded investigator and blinded patient demonstrated higher success
and better patient satisfaction than the control. This is useful
information however is biased due to unblinding of the investigator and
lack of effective blinding of the patient as demonstrated by the
blinding assessment.

[Objective 2]{.underline} (primary objective) To explore whether the
safety of Artecoll as an injectable implant for correction of contour
deformities of the dermis of the face

Based on the information provided in this executive summary, the panel
should address:

-   The level of safety required for a cosmetic device

-   Whether this objective was met for Artecoll based on the information
    presented

[Objective 3]{.underline} (a secondary objective) To characterize the
initial quality of the cosmetic correction provided by Artecoll and
Zyplast/Zyderm.

The study attempted to characterize the initial quality of cosmetic
correction by the devices as per the patients' satisfaction,
investigator assessment and masked observer FFA scale rating. Each of
these assessment tools has associated flaws whether it be bias,
differences in observation from photos versus in-person assessment,
baseline severity, use of the FFA scale in methods that have not been
validated, or level of expectation.

[Objective 4]{.underline} (a secondary objective) of the study is to
characterize the investigator assessment of success with respect to how
closely the treatment met the investigator's initial expectations for
correction.

This is a vague objective as the investigators assessment of success was
based on the investigator's initial expectations for correction. The
investigator's initial expectations for correction were never defined in
the protocol.

[Objective 5]{.underline} (a secondary objective) is to characterize the
subject's assessment of satisfaction with respect to the subject's
personal expectations.

This is a vague objective as the subjects' assessment of success was
based on their initial expectations for correction. The subjects'
initial expectations for correction were never defined in the protocol.

> **[PART III]{.underline}**

**I. Rofil Clinical Study**

> a\. Background -- This study was intended to evaluate the safety and
> effectiveness of Artecoll when used for cosmetic correction. However,
> the originally approved protocol did not involve a control group, and
> the ratings made by the investigators were based on improvement rather
> than objective measurement. The protocol changed significantly during
> the process of obtaining unconditional approval. Also, the method of
> capturing efficacy data was too subjective to be adequate, and the
> number of subjects and areas treated were not sufficient to be
> considered statistically significant.
>
> For all of these reasons, the primary focus of the analysis of the
> Rofil study has been to obtain the safety of Artecoll when used for
> cosmetic correction.
>
> b\. Design -

-   Open label study

-   Uncontrolled

    a.  Inclusion/Exclusion

+-----------------------------------+-----------------------------------+
| ### Inclusion                     | **[Exclusion]{.underline}**       |
+-----------------------------------+-----------------------------------+
| -   Subjects 18 years of age or   | -   Subjects who had been treated |
|     older                         |     with collagen, Botulinum      |
|                                   |     toxin, or other wrinkle/fold  |
| -   In the opinion of the         |     therapies within the last six |
|     investigator, the subjects    |     months at any intended        |
|     has realistic expectations of |     implant area                  |
|     the benefit and limitation of |                                   |
|     the augmentation procedure    | ```{=html}                        |
|                                   | <!-- -->                          |
| -   Subjects presenting for       | ```                               |
|     correction of dermal contour  | -   Subjects who were receiving   |
|     deformities of the face: -    |     current treatment with        |
|     Glabellar Frowns/Folds        |     corticosteroids subdermally,  |
|                                   |     intradermally or              |
|     -   Nasolabial Folds          |     epiperiostally                |
|                                   |                                   |
|     -   Perioral Lines )          | -   Subjects receiving UV light   |
|                                   |     therapy                       |
|     -   Depressed Corners of the  |                                   |
|         Mouth                     | -   Subjects presenting with a    |
|                                   |     personal or family history of |
|                                   |     autoimmune disorder           |
|                                   |                                   |
|                                   | -   Subjects presenting with      |
|                                   |     atrophic skin diseases        |
|                                   |                                   |
|                                   | -   Subjects with thin and        |
|                                   |     flaccid skin                  |
|                                   |                                   |
|                                   | -   Subjects with known           |
|                                   |     susceptibility to keloids     |
|                                   |                                   |
|                                   | -   Subjects with known allergy   |
|                                   |     to collagen                   |
|                                   |                                   |
|                                   | -   Subjects requiring correction |
|                                   |     of atrophy or defects in the  |
|                                   |     subcutaneous fat              |
|                                   |                                   |
|                                   | -   Subjects requiring correction |
|                                   |     of crow's feet                |
+-----------------------------------+-----------------------------------+

> d\. Treatment Protocol
>
> 1\. Treatment areas included:
>
> Glabellar Folds
>
> Nasolabial folds
>
> Perioral lines
>
> Depressed mouth corners

2.  Each subject received as many as 6 facial treatment areas (3 of the
    4 per side) as deemed appropriate by the investigators

> e\. Follow-up Protocol - Subjects had follow-up assessments at 3, 6,
> and 12 months following the last treatment session.

**II. Rofil Medical Study Conduct**

-   157 patients were treated with Artecoll

-   One year safety data was obtained for 126 of the 157 patients
    treated

+-----------------+---------+---------+---------+----------+----------+
| Patient         |         |         |         |          |          |
| Accounting -    |         |         |         |          |          |
| Rofil Study     |         |         |         |          |          |
+-----------------+---------+---------+---------+----------+----------+
|                 | Preop   | Intraop | 3       | 6 months | 12       |
|                 |         |         | months  |          | months   |
+-----------------+---------+---------+---------+----------+----------+
| #####           | 167     |         |         |          |          |
|  Theoretical^1^ |         |         |         |          |          |
+-----------------+---------+---------+---------+----------+----------+
| Device          | 0       | 0       | 0       | 0        | 0\*      |
| removals,       |         |         |         |          |          |
| (cumulative)    |         |         |         |          |          |
+-----------------+---------+---------+---------+----------+----------+
| Expected^2^     | 167     | 167     | 167     | 167      | 167      |
+-----------------+---------+---------+---------+----------+----------+
| Lost to         | 5       | 0       | 24      | 6        | 2        |
| follow-up       |         |         |         |          |          |
| (cumulative)    |         |         |         |          |          |
+-----------------+---------+---------+---------+----------+----------+
| Aborted study   | 5       | 0       | 0       | 0        | 0        |
| (includes not   |         |         |         |          |          |
| treated and     |         |         |         |          |          |
| voluntary       |         |         |         |          |          |
| withdrawal)     |         |         |         |          |          |
| (cumulative)    |         |         |         |          |          |
+-----------------+---------+---------+---------+----------+----------+
| Evaluated^3^    | 157     | 157     | 133     | 127      | 125      |
+-----------------+---------+---------+---------+----------+----------+
| \% Expected     | 100%    | 100%    | 100%    | 100%     | 100%     |
| Follow-up       |         |         |         |          |          |
|                 | 167/167 | 167/167 | 167/167 | 167/167  | 167/167  |
+-----------------+---------+---------+---------+----------+----------+
| ##### Actual    | 94%     | 94%     | 80%     | 76%      | 75%      |
|  % Follow-up^4^ |         |         |         |          |          |
|                 | 157/167 | 157/167 | 133/167 | 127/167  | 125/167  |
+-----------------+---------+---------+---------+----------+----------+

\*2 excisions after 12 month time period

1\. Theoretical = Patients enrolled in the study

2\. Expected = Theoretical -- Device removals

3\. Evaluated = Theoretical -- (Failures+ Lost to Follow-Up + Aborted)

4\. As per evaluated^3^

**III. Rofil Medical Study Results**

Onset of Adverse Events -- Rofil Study

+-------------+---------+------+-------+--------+---------+---------+
|             | **24-48 | **1  | **1   | **3    | **6     | **12    |
|             | hours** | we   | mo    | mo     | m       | m       |
|             |         | ek** | nth** | nths** | onths** | onths** |
+-------------+---------+------+-------+--------+---------+---------+
| **Number of | NA      | NA   | NA    | 133    | 127     | 125     |
| patients    |         |      |       |        |         |         |
| evaluated** |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Total     | 6       | 2    | 1     | 3      | 5       | 3       |
| number of   |         |      |       |        |         |         |
| patients    |         |      |       |        |         |         |
| with        |         |      |       |        |         |         |
| adverse     |         |      |       |        |         |         |
| events**    |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Total     | 7       | 2    | 1     | 3      | 6       | 6       |
| number of   |         |      |       |        |         |         |
| adverse     |         |      |       |        |         |         |
| events**    |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Lumpiness | 2       | 2    | 0     | 0      | 1       | 0       |
| at          |         |      |       |        |         |         |
| injection   | (2      |      |       |        |         |         |
| area more   | esti    |      |       |        |         |         |
| than one    | mated?) |      |       |        |         |         |
| month after |         |      |       |        |         |         |
| injection** |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| *           | 1 (1    | 0    | 0     | 0      | 2       | 0       |
| *Persistent | esti    |      |       |        |         |         |
| swelling or | mated?) |      |       |        |         |         |
| redness**   |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Increased | 1 (1    | 0    | 0     | 0      | 0       | 0       |
| sensi       | esti    |      |       |        |         |         |
| tivity^2^** | mated?) |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Rash,     | 0       | 0    | 0     | 2      | 1 (1    | 1 (1    |
| itching     |         |      |       |        | esti    | esti    |
| more than   |         |      |       |        | mated?) | mated?) |
| 48 hours    |         |      |       |        |         |         |
| after       |         |      |       |        |         |         |
| injection** |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Blurred   | 0       | 0    | 0     | 0      | 0       | 0       |
| vision**    |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Flu-like  | 0       | 0    | 0     | 0      | 0       | 0       |
| symptoms**  |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| *           | 0       | 0    | 0     | 0      | 0       | 0       |
| *Recurrence |         |      |       |        |         |         |
| of existing |         |      |       |        |         |         |
| herpes      |         |      |       |        |         |         |
| labialis**  |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Se        | 1 (1    | 0    | 0     | 0      | 1       | 0       |
| nsitization | esti    |      |       |        |         |         |
| rea         | mated?) |      |       |        |         |         |
| ctions^1^** |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Abscess** | 0       | 0    | 0     | 0      | 0       | 0       |
+-------------+---------+------+-------+--------+---------+---------+
| *           | 0       | 0    | 0     | 0      | 0       | 0       |
| *Visibility |         |      |       |        |         |         |
| of the      |         |      |       |        |         |         |
| puncture    |         |      |       |        |         |         |
| area**      |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Granuloma | 0       | 0    | 0     | 1      | 0       | 2 (1    |
| or          |         |      |       |        |         | after   |
| enlargement |         |      |       |        |         | 12      |
| of the      |         |      |       |        |         | months) |
| implant**   |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **          | 0       | 0    | 0     | 0      | 0       | 0       |
| Infection** |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Other     | 0       | 0    | 0     | 0      | 1       | 3 (2    |
| local       |         |      |       |        |         | es      |
| complic     |         |      |       |        |         | timated |
| ations^2^** |         |      |       |        |         | after   |
|             |         |      |       |        |         | 12      |
|             |         |      |       |        |         | months) |
+-------------+---------+------+-------+--------+---------+---------+
| **Other     | 2       | 0    | 0     | 0      | 0       | 0       |
| systemic    |         |      |       |        |         |         |
| complic     |         |      |       |        |         |         |
| ations^2^** |         |      |       |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+
| **Severe    | 0       | 0    | 1 --  | 0      | 0       | 0       |
| illness,    |         |      | b     |        |         |         |
| trauma,     |         |      | reast |        |         |         |
| death**     |         |      | c     |        |         |         |
|             |         |      | ancer |        |         |         |
+-------------+---------+------+-------+--------+---------+---------+

1\. As defined per each investigator.

2 Local complications - "redness and visible capillaries in NF" and
"patchy complete alopecia areata on head at 3 mos".

3 Systemic complications - "mild chest congestion after both treatment
sessions."

Duration of Adverse Events:

See Attachment 2c: Duration of Adverse Events -- Rofil Study

*Based on the Duration of Adverse events attachment 2c, the top 3
specific adverse events occurring on a per incident basis in the Rofil
treated patients were lumpiness more than 1 month post-injection,
persistent swelling or redness, and granuloma or enlargement of the
implant.*

*For Rofil treated patients, these events lasted over 3 months in:*

-   *4/5 patients found to have lumpiness more than 1 month post
    injection*

-   *1/3 patients found to have persistent swelling or redness*

-   *1/1 patient granulomas or enlargement of the implant*

**[PART IV]{.underline}**

**I. Product Description**

The test material is a 3.5% purified bovine collagen manufactured by
European Medical Contract Manufacturing. The specific formulation is
3.5% collagen, 2.7% phosphate buffer, 0.3% sodium chloride, and 0.3%
lidocaine hydrochloride and 93.2% WFI. Test material is provided sterile
and nonpyrogenic in a prefilled 1.0 cc syringe with 0.1cc of collagen
solution.

**II. Bovine Collagen Immunogenicity Study**

a.  Design

-   Single investigator, prospective, open-label non-controlled clinical
    trial

-   To determine the safety and immunogenicity of the bovine collagen in
    Artecoll because collagen source for the proposed commercial product
    differs from the collagen component used in the large scale clinical
    study (i.e., the Artes Study).

b.  Inclusion/Exclusion Criteria

+----------------------------------+-----------------------------------+
| ### Inclusion                    | **[Exclusion]{.underline}**       |
+----------------------------------+-----------------------------------+

+--------------------------------+-------------------------------------+
| -   Subjects 35 years of age   | -   Subjects who are pregnant       |
|     of older, of either sex    |                                     |
|                                | ```{=html}                          |
| ```{=html}                     | <!-- -->                            |
| <!-- -->                       | ```                                 |
| ```                            | -   Subjects who have had collagen  |
| -   Subjects wiling and able   |     treatment within the last 3     |
|     to comply with study       |     months                          |
|     requirements               |                                     |
|                                | -   Subjects who were treated with  |
| -   Subjects willing and able  |     chemotherapy agents or          |
|     to comply study follow-up  |     corticosteroids within the past |
|     requirements               |     3 months                        |
|                                |                                     |
| -   Subjects willing and able  | -   Subjects with a history of      |
|     to give informed consent   |     autoimmune disorder             |
|                                |                                     |
|                                | -   Subjects with known lidocaine   |
|                                |     hypersensitivity                |
|                                |                                     |
|                                | -   Subjects with known sensitivity |
|                                |     to bovine collagen              |
|                                |                                     |
|                                | -   Subjects who have a history of  |
|                                |     dietary beef, undergoing        |
|                                |     desensitization to beef         |
|                                |     products or planning to undergo |
|                                |     desensitization within the      |
|                                |     study evaluation period.        |
|                                |                                     |
|                                | -   Subjects with severe allergies  |
|                                |     manifested by a history of      |
|                                |     anaphylaxis                     |
|                                |                                     |
|                                | -   Subjects with a current disease |
|                                |     state that can effect the       |
|                                |                                     |
|                                | -   immunoresponse (e.g., flu,      |
|                                |     cancer, HIV)                    |
|                                |                                     |
|                                | -   Subjects who are currently      |
|                                |     treated with immunosuppressive  |
|                                |     drugs                           |
+--------------------------------+-------------------------------------+

> c\. Treatment Protocol

1.  Subjects screened

2.  If entry criteria met then patient had a pre-injection serum sample
    drawn

3.  The physician then injected 0.1 ml of a collagen solution
    intra-dermally in the volar forearm

4.  The physician then assessed the test site for an acute reaction for
    15-30 minutes after the injection

5.  The subject was permitted to go home and was instructed to observe
    the test site daily for 30 days and notified the investigator if any
    effects indicative of a positive response were observed or systemic
    effects were experienced. The subject received both written
    instructions for assessing the test site and a "Patient Skin
    Response Sheet"

6.  30 days after the first injection the subjects returned to the
    clinic. If the investigator determined that the subject displayed a
    positive response, the subject's participation in the study was
    completed and a final blood drawn was taken.

7.  If the subject did not display a positive response to the first
    collagen injection, they received a second 0.1 ml injection
    intradermally in the contra lateral volar forearm.

8.  The physician then assessed the test site for an acute reaction for
    15-30 minutes after the injection after which the subject went home
    and observed the test site daily for 30 days. The subjects were
    instructed to notify the investigator if any effects indicative of a
    positive skin test response or systemic effects were experienced.
    The subjects also recorded observations in a "Patient Skin Response
    Sheet"

> d\. Follow-up Protocol

-   Visit 2 30 days following initial skin test

-   Visit 3 following 2^nd^ skin test

-   Daily evaluations by patient

> e\. Follow-up Assessment Method
>
> 1\) Skin test results - The injection site was evaluated to determine
> negative, positive or equivocal response:

-   [Negative]{.underline} = No localized skin reaction and the patient
    has no systemic reaction

-   [Positive]{.underline} = Erythema of any degree, induration,
    tenderness, rash and swelling with or without pruritis, which can
    appear immediately following implantation and persists for more than
    24 hours or appears more than 24 hours following implantation

-   [Equivocal]{.underline} =No localized skin reaction but the patient
    does elicit a possible systemic reaction such as rash, arthralgia,
    or myalgia which occurs at any time during the 30 (+/- 5) day
    observation period.

> 2\) Abnormal Serum IgG Test Results - the number of patients
> exhibiting a normal serum IgG level before administration of the skin
> test and the an abnormally high serum IgG at the time of the second
> blood draw
>
> 3\) Adverse events
>
> f\. Study Purpose and Objective
>
> [Purpose]{.underline} To determine the frequency of positive collagen
> skin test results for a new Artecoll collagen source.
>
> [Objective]{.underline} To provide information that can be used in
> labeling to be submitted to the US Food and Drug Administration and
> other regulatory bodies in connection with applications for marketing
> approval.

**III. Bovine Collagen Study Conduct**

> a\. Enrollment

-   235 subjects were injected with bovine collagen.

-   225 subjects completed the study per protocol.

> b\. Demographics

+-----------------------------------+-----------------------------------+
| **N = 235**                       |                                   |
+-----------------------------------+-----------------------------------+
| **Gender**                        |                                   |
+-----------------------------------+-----------------------------------+
| > Male                            | 78 (32.8%)                        |
+-----------------------------------+-----------------------------------+
| > Female                          | 157 (67.2%)                       |
+-----------------------------------+-----------------------------------+
| **Mean Age**                      | 48.2 years                        |
+-----------------------------------+-----------------------------------+
| **Ethnicity**                     |                                   |
+-----------------------------------+-----------------------------------+
| > Caucasian                       | 188 (80.0 %)                      |
+-----------------------------------+-----------------------------------+
| > Hispanic                        | 32 (13.6 %)                       |
+-----------------------------------+-----------------------------------+
| > Black                           | 11 (4.7 %)                        |
+-----------------------------------+-----------------------------------+
| > Asian                           | 2 (0.085%)                        |
+-----------------------------------+-----------------------------------+
| > Black & Hispanic                | 1 (0.042%)                        |
+-----------------------------------+-----------------------------------+
| > Native American                 | 1 (0.042%)                        |
+-----------------------------------+-----------------------------------+

> c\. Accountability

+-----------------+---------+---------+---------+-----------+---------+
| Patient         |         |         |         |           |         |
| Accounting      |         |         |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
| Time of:        |         | In      |         | Injection |         |
|                 |         | jection |         | 2         |         |
|                 |         | 1       |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
|                 | S       | E       | Visit 1 | Visit 2   | Visit 3 |
|                 | creened | nrolled |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
| Expected^1^     | 244     | 235     |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
| Lost to         | 0       | 0       | 0       | 7         | 2       |
| follow-up       |         |         |         |           |         |
| (cumulative)^3^ |         |         |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
| Aborted study   | 0       | 0       | 0       | 0         | 1       |
| (includes not   |         |         |         |           |         |
| treated and     |         |         |         |           |         |
| voluntary       |         |         |         |           |         |
| withdrawal)     |         |         |         |           |         |
| (cumulative)^4^ |         |         |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
| Evaluated^5^    | 244     | 235     | 235     | 228       | 225     |
+-----------------+---------+---------+---------+-----------+---------+
| Experienced     | 0       | 0       | 0       | 5         | 8       |
| skin reaction   |         |         |         |           |         |
| but were not    |         |         |         |           |         |
| discontinued    |         |         |         |           |         |
|                 |         |         |         |           |         |
| (cumulative)    |         |         |         |           |         |
+-----------------+---------+---------+---------+-----------+---------+
| ##### Actual    | 100%    | 100%    | 100%    | 97%       | 97.5%   |
|  % Follow-up^6^ |         |         |         |           |         |
|                 | 244/244 | 235/235 | 235/235 | 228/235   | 225/235 |
+-----------------+---------+---------+---------+-----------+---------+

1\. Expected = Patients enrolled in the study

2\. Of the patients lost to follow-up, 5/9 were contacted and reported
no local skin reaction

> 3\. Patient violated the exclusion criteria, but had no skin test
> reaction or abnormal elevation in serum IgG levels.

4\. Evaluated = Theoretical -- (skin reactions+ Lost to Follow-Up +
Aborted)

5\. As per evaluated

**IV. Study Results**

a\. Positive Skin Tests Responses --

  -------------- -------------- -------------- -------------- --------------
                 Within 15-30   Within 30 days Within 15-30   Within 30 days
                 minutes Post   Post Injection minutes Post   Post Injection
                 Injection 1    1              Injection 2    2

  Number of      0              4              1              3
  patients with                                               
  positive skin                                               
  test (8                                                     
  patients of                                                 
  235 studied =                                               
  3.4%)                                                       
  -------------- -------------- -------------- -------------- --------------

b\. Adverse Events

Time to onset of Adverse Events

  ----------------- ----------------- ----------------- -----------------
  **Category**      **24-48 hours**   **1 week**        **1 month**

  Number of         235                                 
  subjects                                              
  evaluated                                             

  Total number of   5                 22                31
  adverse events                                        

  Total number of   5                 18                26
  patients with                                         
  adverse events                                        

  Arm tingling,     1                 0                 0
  warmth, clammy                                        

  Broken toe        0                 1                 0

  Broken wrist      0                 0                 1

  Cataract surgery  0                 0                 1

  Cellulitis        0                 1                 0

  Cough             0                 1                 3

  Dental extraction 0                 0                 1

  Diarrhea          0                 3                 0

  Facial and Hand   0                 1                 0
  Edema                                                 

  Flu Symptom       0                 0                 1

  Headache          1                 0                 1

  Increased         1                 0                 0
  perspiration                                          

  Irritant          1                 0                 0
  dermatitis                                            

  Lymphadenopathy   1                 0                 0

  Migraine Headache 0                 0                 1

  Muscle Ache       0                 1                 0

  Recurrent Herpes  0                 1                 0
  simplex virus                                         

  Recurrent oral    0                 0                 1
  herpes simplex                                        
  virus                                                 

  Rhinitis          0                 0                 1

  Sinus congestion  0                 1                 1

  Sore throat       0                 0                 2

  Stomach Ache      0                 0                 1

  Swollen glands    0                 1                 0
  right neck                                            

  Tooth infection   0                 0                 1

  Torn ligament     0                 0                 1
  right foot                                            

  Upper respiratory 0                 8                 13
  infection                                             

  Urinary tract     0                 0                 1
  infection                                             

  Vomiting          0                 3                 0
  ----------------- ----------------- ----------------- -----------------

Duration of Adverse Events

> See attachment 2d: Bovine Collagen Immunogenicity Study -- Duration of
> Adverse Events

c\. Serum Levels of Bovine Collagen Antibodies

> The Center testing laboratory defined the normal serum IgG range as a
> titer between 700 and 1,600. No subjects transitioned from the normal
> serum IgG level before administration to an abnormally high serum IgG
> level in the post-treatment blood sample.

**V. Did the Study Meet Its Purpose and Objective?**

> [Purpose]{.underline} To determine the frequency of positive collagen
> skin test results for a new Artecoll collagen source.
>
> *The incidence of a positive skin response was found to be 3.4%. The
> incidence of equivocal skin test results as prospectively defined is
> not well characterized and should be assessed by examination of
> adverse events.*
>
> [Objective]{.underline} To provide information that can be used in
> labeling to be submitted to the US Food and Drug Administration and
> other regulatory bodies in connection with applications for marketing
> approval.
>
> *The information provided can be used in device labeling.*
>
> *Of note, the labeling of ZYDERM collagen implant states that the
> incidence of positive test site response or similar systemic responses
> as described here has been approximately 3.0%.*