# 3. SUMMARY OF SAFETY AND EFFECTIVENESS

# 3.1 General Information

**[Device Generic Name]{.underline}**: Interactive Wound and Burn
Dressing

**[Device Trade Name]{.underline}**: Composite Cultured Skin

**[Applicant's Name and Address]{.underline}**: Ortec International,
Inc.

3960 Broadway, 2^nd^ Flr.

> New York City, NY 10032

**[Date of Panel Recommendation]{.underline}**:

**[Date of Notice of Approval of Application]{.underline}**:

# 

# 3.2 Indications For Use

Composite Cultured Skin is indicated for use in accelerating wound
closure of split thickness donor site wounds in burn patients.

# 3.3 Device Description

Composite Cultured Skin is composed of a collagen matrix in which
allogeneic human skin cells, (i.e., epidermal keratinocytes and dermal
fibroblasts) are cultured in two distinct layers. The collagen
cross-linked sponge consists primarily of Type I bovine collagen
laminated on one side with a thin gel layer of acid-soluble bovine
collagen.

The device is manufactured under aseptic conditions from human neonatal
male foreskin tissue. The donor's mother is tested and found to be
negative for syphilis and for human viruses, including HTLV I&II,
Hepatitis B&C, HIV 1&2, EBV and HHV-6. The donor's fibroblast and
keratinocyte cells are tested for human viruses (and found to be
negative for HTLV I&II, Hepatitis B, HIV 1&2, EBV, and HHV-6),
retroviruses, bacteria, fungi, yeast, mycoplasma, karyology, isoenzymes,
tumorigenicity, normal growth and morphology. The final product is
tested for morphology, cell viability, sterility, mycoplasma, and
physical container integrity. Product manufacture also includes
animal-derived reagents, which are tested and found to be negative for
viruses, retroviruses, bacteria, fungi, yeast, and mycoplasma before use
and all bovine material is obtained from countries free of Bovine
Spongiform Encephalopathy (BSE).

The device measures approximately 6 cm x 6 cm (minimally 36 cm^2^). A
non-adherent mesh (N-Terface® (Winfield Laboratories, Inc., Dallas,
Texas)) is placed on both aspects of the device to protect the cells.
The device is packaged in a plastic tray with protein-free packaging
medium containing DMEM, water for irrigation, sodium bicarbonate, folic
acid solution, HEPES buffer, L-Glutamine, MEM non-essential amino acids,
and sodium hydroxide to maintain cell viability during storage and
shipping.

The plastic tray is sealed within a peelable inner pouch to provide a
sterile barrier against moisture and gas. The inner pouch is, in turn,
sealed inside a heavier-gauge outer pouch that protects the inner pouch
sterility barrier and the product against damage during shipment. The
multi-stage packaged product is packed with pre-chilled gel packs and
shipped to the destination in a padded and insulated shipping container
that maintains a temperature of 11-18° C (for up to 72 hr.).

# 3.4 Contraindications

-   Composite Cultured Skin is contraindicated for use on clinically
    infected wounds (see Precautions).

-   Composite Cultured Skin is contraindicated in patients with known
    allergies to bovine collagen.

**3.5** **Alternative Practices And Procedures**

Split thickness skin grafting is a frequently used technique in the
management of serious skin injuries requiring skin replacement, such as
burns. Once it has been determined that a patient will require split
thickness autografting, the creation of a donor site is automatically
necessitated. Donor sites are areas of healthy, non-injured skin, which
are harvested for autograft use, thereby leaving an open wound requiring
coverage. CCS treatment of donor sites is the subject of this
application.

There are many dressing options for donor sites in the postoperative
period. The type of dressing selected depends on the size of the donor
site created, the anatomic location on the body surface, and the
proximity to other wounds. Types of dressings include biologic and
biosynthetic wound dressings, and synthetic skin substitutes which
permit wound healing in a moist environment.

An alternative technique is to use a dry, fine-meshed gauze or gauze
impregnated with petrolatum or antimicrobial agents to cover these donor
sties. These dressings are more painful to the patient and, when dry,
prolong wound healing and do not permit motion of involved areas as
effectively as moist or occlusive dressings.

# 3.6 Marketing History

Composite Cultured Skin has been approved under a Humanitarian Device
Exemption for use in patients with mitten hand deformity due to
Recessive Dystrophic Epidermolysis Bullosa (RDEB) as an adjunct to
standard autograft procedures (i.e., skin grafts and flaps) for covering
wounds and donor sites created after the release of hand contractions
(i.e., "mitten" hand deformities).

No launch date has been set as of the cut-off date for this PMA.

CCS is not marketed nor has it been withdrawn from marketing in any
other country.

# 3.7 Summary of Studies

# 3.7.1 Summary of Nonclinical Laboratory Studies 

To establish the efficacy of CCS and the safety of the collagen sponge
coated with collagen gel, Ortec International has conducted a series of
studies. Wound healing was examined in severe combined immuno-deficient
(SCID) mice, athymic nude mice, and swine. Cytokine production was
examined *in vitro*, and biocompatibility studies were performed in
rabbits, mice, and guinea pigs. An overview of the nonclinical studies
conducted on CCS and the acellular collagen sponge is presented below.

CCS is designed to enhance wound healing in part by release of
cytokines. In an *in vitro* assay, CCS stimulated the release of
cytokines into culture media. *In vivo* wound healing was examined in
male severe combined immuno-deficient (SCID) mice and female athymic
nude mice. For male SCID mice, CCS produced approximately 60% wound
contracture and complete epithelialization in eight of twelve animals.
In a range-finding study using CCS with different cell densities, a
trend toward greater wound healing was observed in nude mice treated
with medium and high cell density CCS than with acellular or low cell
density CCS.

The collagen sponge coated with collagen gel was shown to be
biocompatible in *in vitro* cytotoxicity and *in vivo* tests under the
conditions of the studies. There was no evidence of cytotoxicity when
extracted material from the coated collagen sponges was incubated with
mouse connective tissue NCTC 929 cells (elution and agar diffusion
assays). An extract of the coated collagen sponge was not a hemolytic
agent when tested in rabbit red blood cells. In guinea pigs, undiluted
extracted material from the coated collagen sponge did not produce
sensitization. Intracutaneous and acute systemic toxicity studies
performed in rabbits and mice, respectively, resulted in comparable
responses between extracts of the collagen sponge coated with collagen
gel and control materials. Similarly, intramuscular implantation of the
coated sponge into rabbits with observations up to 90 days
post-implantation resulted in no significant differences between the
control material and coated sponge. Both produced negative to mild
reactivity, but the collagen sponge coated with collagen gel was more
rapidly resorbed. The coated sponge was not mutagenic, and an extract of
the coated collagen sponge did not produce a pyrogenic response in
rabbits.

A full thickness skin wound study was conducted in swine comparing the
healing rates for the collagen sponge and control material. Skin wounds
made in swine revealed similar rates of healing for collagen sponges and
the control material; complete resorption of the sponge was reported by
day 30.

Data collected in murine models of full-thickness wound healing revealed
60% wound contracture and complete epithelialization in 67% of male SCID
mice at 14 days post-treatment with CCS, and a trend toward greater
wound healing with higher cell densities of CCS in female nude mice. In
an *in vitro* assay, several of the cytokine expression levels measured
in CCS, such as GM-CSF and VEGF, lead to accumulated concentrations in
CCS culture medium in the nanogram per milliliter level, which is
significant.

With respect to biocompatibility, i*n vitro* assays confirmed a lack of
cytotoxicity and hemolysis. And, extracted material from the coated
sponge did not produce sensitization, mutagenicity, pyrogenicity, or
adverse intracutaneous, acute systemic, or sustained intramuscular
effects. In a swine model, comparable resorption and healing were
observed between control materials and the collagen sponge.

## 

### 

## 

## 

## 

## 

## 

## 

## 3.7.2 Summary of Clinical Studies 

### Donor Site Pilot Study in Burn Patients

*Protocol #97-002/OR "A Controlled Randomized Pilot Study of the Effects
of a Composite Cultured Skin Containing a Collagen Matrix Seeded with
Allograft Cells on the Management of Split Thickness Donor Sites".*

#### Study Design

This study was a prospective, single-center, open, randomized and
controlled trial in patients requiring split thickness skin autografting
for the management of burn injuries. This was a matched-pairs design
(i.e., each patient had two designated donor sites of equivalent surface
area). Each site was randomized to receive a single application of
either CCS or the control dressing. Patients were followed through
post-treatment Day 28.

#### Patient Assessment

The primary outcome measure was the time (days) to wound closure (100%
re-epithelialization). Re-epithelialization was defined as the visible
presence of a dry, opalescent-pink external surface representing the
newly formed outer cornified layer of the epidermis, which, in the
Investigator's assessment, no longer required a dressing or protective
covering. Wound closure was evaluated using computerized planimetric
analysis and validated through photographic review. Photographs were
assessed by two blinded independent burn experts to determine if
clinical re-epithelialization was present.

The secondary outcome measures included the time to complete wound
closure (Investigator's assessment), the rate of healing, and the time
to readiness for recropping. This latter measure reflected the quality
of healing (i.e., the time at which reharvesting would be clinically
possible).

Safety was assessed by recording adverse events, donor site pain and
itching assessments, and the incidence of infection, wound cultures, and
laboratory measurements.

#### Disposition of Patients/Demography 

A total of eight subjects were enrolled into a single center. Seven
patients completed the study and one patient had a serious adverse
event, which resulted in death and that was judged by the Investigator
to be unlikely related to study treatments.

Five (62.5%) patients were African American, and three (37.5%) were
Caucasian. Mean age of the patients was 41.3 years (range 10 to 84
years); mean height was 66.8 inches (range 51 to 72 inches); and mean
weight was 145.1 pounds (range of 83 to 221 pounds).

#### Analysis and Results

Efficacy Results

*Healing at graft site- Planimetric Analysis and Investigator's
Assessment.* The Kaplan-Meier estimates of the percent of healed
patients from computerized planimetric analysis and from the
Investigator's assessment showed a statistically significant difference
in healing time between CCS and the control treatment (p=0.034), with
shorter healing times observed with CCS. At least 50% of the patients
were healed by both planimetric analysis and Investigator's assessment
by Day 12 with CCS, while 50% of the patients were healed by Day 25 with
the control treatment.

The healing rate from the Investigator's assessment of the percent of
healing at each visit was calculated. At each time point, the mean
percentages of CCS donor site healing were larger than the mean
percentages for the control site. At Days 14 and 21, these differences
were statistically significant (p=0.014 and 0.026, respectively).

*Readiness for recropping assessments*. At the end of the study, the
Investigator assessed the CCS sites to be ready for recropping. CCS
sites were ready for recropping before the control sites in three
patients, for one patient, both sites were ready at the same time, and
for two patients, neither site was ready.

*Photographs*. The photographs were evaluated by blinded reviewers.
Overall, the majority of the validation and inter-observer correlation
results indicated substantial agreement between the various assessment
methods (computerized planimetric analysis, the Investigator's
assessments, and the blinded review of the photographs).

Safety Results

All eight patients had at least one adverse event. One patient died and
12 serious adverse events were reported and all were considered by the
Investigator to be unlikely related to study treatment. The highest
incidences of adverse events were fever and constipation (each with 3
patients (37.5%)).

There were no statistically significant differences in donor site pain
or itching between the two treatments at any of the study time points.

Donor Site Pivotal Study in Burn Patients

*Protocol #98-004/OR: "Controlled Randomized Multi-Center Study of the
Effects of a Composite Cultured Skin Containing a Collagen Matrix Seeded
with Allograft Cells on the Management of Split Thickness Donor Sites in
Burn Patients".*

#### Study Design

This was a prospective, active controlled, randomized multi-center study
involving patients requiring conventional split thickness skin
autografting for the management of burn injuries. The study incorporated
a matched pairs design (i.e., each patient had two designated donor
sites of equivalent surface area and depth). Each donor site was
randomized to receive a single treatment of either the control dressing
or investigational device (CCS).

#### Patient Assessment 

The primary efficacy variable was time to complete wound closure
(complete re-epithelialization) as determined by photography.

The secondary efficacy variables were time to complete wound closure as
determined by computerized planimetric assessment of unhealed wounds,
time to complete wound closure as determined by investigator through
clinical assessment, the rate of wound healing as determined by the
percent change in wound area from baseline as determined by planimetric
data, time to readiness for recropping as assessed by the investigator,
and time to actual recropping of an original donor site.

Safety variables that were compared between the two treatments were:
incidence of donor site specific adverse events, scar outcome, pain and
itching scores, and incidence of donor site infection and breakdown,
time to actual recropping, and recrop outcome. Adverse events were
tabulated by preferred term, body system and severity (mild, moderate,
severe, life-threatening or fatal).

#### Disposition of Patients/Demography 

#### 

#### A total of 82 patients were enrolled among 12 study sites. All 82 patients were included in the intent-to-treat and safety populations. The per-protocol population consisted of 74 patients (90.2%). Sixty patients (73%) completed the study, 22 patients (26.8%) discontinued study before the week 24 visit, and 8 patients were excluded from the per protocol analysis.

The population receiving randomized treatment was composed of 63 men
(76.8%) and 19 (23.2%) women. Mean age of all patients was 31.7 years
(range: 1 to 88 years). The population was 53.7% Caucasian, 24.4%
African-American, 15.9% Hispanic, 2.4% Asian/Pacific Islander and 3.7%
other.

#### Analysis and Results

All patients who were randomized and received treatment with the study
devices, regardless of study completion, and had at least one
post-treatment efficacy evaluation were included in the intent-to-treat
(ITT) population. The population included in the safety analysis was the
subset of the intent-to-treat population who received treatment with a
study device, regardless of study completion. Included in the
per-protocol population were patients who received treatment with a
study device and who had no major protocol violations.

[Efficacy Results]{.underline}

Primary efficacy data (i.e., time to 100% wound closure) are presented
in Table 3.7.2.1 for the ITT and PP populations and the three methods of
assessment.

######### Table 3.7.2.1: Median and Mean Days to 100% Wound Closure

<table>
<colgroup>
<col style="width: 17%" />
<col style="width: 7%" />
<col style="width: 9%" />
<col style="width: 8%" />
<col style="width: 10%" />
<col style="width: 3%" />
<col style="width: 8%" />
<col style="width: 11%" />
<col style="width: 12%" />
<col style="width: 13%" />
</colgroup>
<tbody>
<tr class="odd">
<td></td>
<td colspan="4"><strong>Median Days to Wound Closure*</strong></td>
<td></td>
<td colspan="4"><strong>Mean (SD) Days to Wound Closure</strong></td>
</tr>
<tr class="even">
<td></td>
<td><strong>Source</strong></td>
<td><strong>CCS</strong></td>
<td><strong>CON</strong></td>
<td><strong>p-value**</strong></td>
<td></td>
<td><strong>Source</strong></td>
<td><strong>CCS</strong></td>
<td><strong>CON</strong></td>
<td><strong>p-value+</strong></td>
</tr>
<tr class="odd">
<td>Investigator ITT</td>
<td>E18.3</td>
<td>12.0</td>
<td>16.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E18.1</td>
<td>13.2(4.87)</td>
<td>18.4(7.86)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="even">
<td>Investigator PP</td>
<td>E19.3</td>
<td>12.0</td>
<td>16.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E19.1</td>
<td>12.9(4.16)</td>
<td>17.9(7.51)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="odd">
<td>Planimetric ITT</td>
<td>E1.3</td>
<td>12.0</td>
<td>17.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E1.1</td>
<td>13.7(5.83)</td>
<td>19.3(8.37)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="even">
<td>Planimetric PP</td>
<td>E2.3</td>
<td>12.0</td>
<td>16.0</td>
<td>&lt;0.0001</td>
<td></td>
<td>E2.1</td>
<td>13.4(5.14)</td>
<td>18.7(8.02)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="odd">
<td>Photographic ITT</td>
<td>E9.3</td>
<td>15.0</td>
<td>22.0</td>
<td>0.0006</td>
<td></td>
<td>E9.1</td>
<td>18.0(7.12)</td>
<td>22.4(8.48)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="even">
<td>Photographic PP</td>
<td>E10.3</td>
<td>15.0</td>
<td>21.0</td>
<td>0.0009</td>
<td></td>
<td>E10.1</td>
<td>17.8(6.64)</td>
<td>22.1(8.25)</td>
<td>&lt;0.0001</td>
</tr>
<tr class="odd">
<td colspan="10"><p>*Kaplan-Meier estimates of the median days to 100%
wound closure +Paired t-test</p>
<p>**Log-Rank test of the difference between median healing
times</p></td>
</tr>
</tbody>
</table>

For the ITT population and median days to healing using photographic
assessment, CCS treated sites healed seven days faster than the control
treated sites (15 days vs. 22 days, respectively); this was
statistically significant with p-value =0.0006. For mean days to healing
by photographic assessment, CCS treated sites in the ITT population
healed four days faster than the control treated sites (18 days vs. 22
days, respectively), also statistically significant (p\<0.0001).

Results of ITT planimetric assessments support those obtained by
photography, i.e., median and mean days to healing for CCS were 12 to 14
days, respectively, while those of the control treated sites were 17 and
19 days, respectively. These differences reflect a five-day shorter time
to healing with CCS and are statistically significant (p=\<0.0001).

Results of the ITT investigator assessment also support those obtained
by photography, i.e., median and mean days to healing for CCS were 12
and 13 days, respectively, while those of the control treated sites were
16 and 18 days, respectively, reflecting a four to five day shorter time
to healing with CCS that is statistically significant (p\<0.0001).

The Per Protocol (PP) population results obtained closely resemble those
of the ITT population with statistically significant differences in time
to wound closure for all three-assessment methods.

[Rate of Wound Closure]{.underline}

Secondary efficacy parameters for the rate of Wound Closure in the ITT
population is depicted in Figure 3.7.2.2 . Clinically meaningful and
statistically significant differences in the rates of wound closure per
day, as measured by planimetry, were observed during the 32-day
post![](media/image5.wmf) surgical period. Results of analyses indicated
that CCS promoted a faster rate of healing than did the control treated
sites. The mean rate of wound closure for CCS on days 6 through 16 was
61% faster than the control treated sites during the same period (6.1 vs
3.8 cm^2^, respectively) and the mean closure time of CCS during day
17-32 was 90% faster than that of the control treated sites (4.0 vs. 2.1
cm^2^, respectively).

[Time to Readiness for Re-Cropping]{.underline}

The time to readiness for re-cropping, as assessed by the investigator,
is depicted for the ITT population in Figure 3.7.2.3. The median time
required for re-crop of a CCS treated site was 7 days less than the
median time required for the control treated site; i.e., 14 days CCS vs.
21 days control treated sites, (p=0.0002). Mean times to readiness for
re-cropping were 5 days less for CCS (i.e., 16 days CCS vs. 21 days
control treated sites \[p\<0.0001\]).

![](media/image6.wmf)

[Scarring Severity]{.underline}

Scarring severity was assessed by two methods. Investigator assessments
were conducted at weeks 12 and 24 and at the follow-up visit using the
Vancouver Scar Scale. Assessments were also conducted via blinded review
of photographs utilizing the Hamilton Burn-Scar Rating Scale. With both
assessment methods, scarring severity at CCS treated sites was
significantly lower (p\<0.05) than the control treated sites at weeks 12
and 24.

![](media/image7.wmf){width="4.55984251968504in"
height="2.4783464566929134in"}Figure 3.7.2.4 depicts the mean Vancouver
scores for the Safety Population, as assessed by the Investigator. At
week 12, mean scarring severity at CCS treated sites was nearly 30% less
than the control treated sites (2.26 versus 3.07, respectively,
p=0.017). At week 24, mean scarring severity for the CCS sites was more
than 30% less than the control treated sites (2.56 versus 3.79,
respectively, p=0.002). At the follow up visit, no statistically
significant difference was observed between the two treatments.

[Signs of Infection and Breakdown]{.underline}

Clinically meaningful differences were noted in signs of infection and
site breakdown between the CCS and the control treated sites, in favor
of CCS. The percentage of CCS donor sites exhibiting signs of infection
was 1.2% versus 3.7% for the control treated sites. The percentage of
CCS donor sites exhibiting signs of breakdown or blistering was 5.0%
compared to 10.1% for the control treated sites.

[Itching]{.underline}

Severity and incidence of donor site itching was similar for the two
groups (72.2% vs. 68.8%, CCS vs. the control treated site,
respectively), with no clinically meaningful or statistically
significant increase in itching for the CCS group.

[Safety Results]{.underline}

Of the 82 patients enrolled in the study, 64 (78.0%) had at least one
adverse event. Overall, most of the adverse events were mild to moderate
in severity, however there were three fatalities that were not related
to treatment of the donor site. Sepsis, multiple organ system failure
and dyspnea were the events associated with fatal outcomes. Serious
adverse events without donor site involvement were reported by 23 (28%)
of the patients. There were no serious adverse events involving the
donor sites. There were 12 adverse events involving the CCS site and 13
adverse events involving the control treated site. All of the adverse
events with donor site involvement were mild to moderate in severity.

Table 3.7.2.5 lists the adverse events without donor site involvement
that had an incidence of [\>]{.underline} 5.0 % in one or more severity
categories. Most of the adverse events were considered unlikely to be
related to the study treatment. No severe, life threatening, or fatal
adverse events occurred at an incidence of [\>]{.underline} 5.0%.

+----------------------------+------+------+------+------+------+------+
| **Table 3.7.2.5: Adverse   |      |      |      |      |      |      |
| Events Reported with an    |      |      |      |      |      |      |
| Incidence [\>]{.underline} |      |      |      |      |      |      |
| 5.0% by Severity**         |      |      |      |      |      |      |
+============================+======+======+======+======+======+======+
|                            | **   |      | **   |      | **   |      |
|                            | Mild |      | Seve |      | Life |      |
|                            | to   |      | re** |      | Thr  |      |
|                            | Mo   |      |      |      | eate |      |
|                            | dera |      | **n= |      | ning |      |
|                            | te** |      | 82** |      | /    |      |
|                            |      |      |      |      | Fat  |      |
|                            | **n= |      |      |      | al** |      |
|                            | 82** |      |      |      |      |      |
|                            |      |      |      |      | **n= |      |
|                            |      |      |      |      | 82** |      |
+----------------------------+------+------+------+------+------+------+
| **Body System**            | n    | \%   | n    | \%   | n    | \%   |
|                            |      |      |      |      |      |      |
| > Preferred Term           |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| **Body As A Whole -        |      |      |      |      |      |      |
| General Disorders**        |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Fever                      | 8    | 9.8  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Gastro-Intestinal System |      |      |      |      |      |      |
| Disorders**                |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Constipation               | 16   | 19.5 | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Nausea                     | 8    | 9.8  | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Vomiting                   | 9    | 11.0 | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Metabolic And            |      |      |      |      |      |      |
| Nutritional Disorders**    |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Hyperglycaemia             | 5    | 6.1  | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Hypernatraemia             | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Platelet,Bleeding &      |      |      |      |      |      |      |
| Clotting Disorders**       |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Thrombocythaemia           | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Psychiatric Disorders**  |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Agitation                  | 6    | 7.3  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Anxiety                    | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Insomnia                   | 12   | 14.6 | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Red Blood Cell           |      |      |      |      |      |      |
| Disorders**                |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Anaemia                    | 11   | 13.4 | 1    | 1.2  | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Reproductive Disorders,  |      |      |      |      |      |      |
| Female** (N=19)            |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Vaginal Haemorrhage (N=19) | 1    | 5.3  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Respiratory System       |      |      |      |      |      |      |
| Disorders**                |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Atelectasis                | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| Pharyngitis                | 8    | 9.8  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Skin And Appendages      |      |      |      |      |      |      |
| Disorders**                |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Pruritus                   | 8    | 9.8  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| **Body System              |      |      |      |      |      |      |
| Unclassified**             |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+
| Relaxation Of Scar         | 5    | 6.1  | 0    |      | 0    |      |
+----------------------------+------+------+------+------+------+------+
| n=Number of Patients       |      |      |      |      |      |      |
+----------------------------+------+------+------+------+------+------+

There were 12 mild to moderate adverse events involving the CCS treated
donor sites and 13 mild to moderate adverse events involving the control
treated donor sites. The events for each treatment, the severity of the
event and its frequency are presented in Table 3.7.2.6

Table 3.7.2.6: Adverse Events Reported With Donor Site Involvement

<table style="width:100%;">
<colgroup>
<col style="width: 33%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 8%" />
<col style="width: 0%" />
<col style="width: 8%" />
</colgroup>
<tbody>
<tr class="odd">
<td rowspan="3"><strong>Adverse Event</strong></td>
<td colspan="4"><strong>CCS</strong> (n=82)</td>
<td colspan="5"><strong>Control</strong> (n=82)</td>
</tr>
<tr class="even">
<td colspan="2"><strong>Mild</strong></td>
<td colspan="2"><strong>Moderate</strong></td>
<td colspan="2"><strong>Mild</strong></td>
<td colspan="3"><strong>Moderate</strong></td>
</tr>
<tr class="odd">
<td><p id="n" class="heading"> n</p></td>
<td>%</td>
<td><p id="n-1" class="heading"> n</p></td>
<td>%</td>
<td><p id="n-2" class="heading"> n</p></td>
<td>%</td>
<td colspan="2"><p id="n-3" class="heading"> n</p></td>
<td>%</td>
</tr>
<tr class="even">
<td>Application site reaction</td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Pain</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td colspan="2">2.4</td>
</tr>
<tr class="even">
<td><p id="infection" class="heading">Infection</p></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Surgical Site Reaction</td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="even">
<td>Bullous Eruption</td>
<td>0</td>
<td></td>
<td>0</td>
<td></td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td>Pruritus</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>2</td>
<td>2.4</td>
<td>3</td>
<td colspan="2">3.7</td>
</tr>
<tr class="even">
<td>Rash Pustular</td>
<td>1</td>
<td>1.2</td>
<td>0</td>
<td></td>
<td>0</td>
<td></td>
<td>0</td>
<td colspan="2"></td>
</tr>
<tr class="odd">
<td colspan="10">n=Number of Patients</td>
</tr>
</tbody>
</table>

## Deaths, Other Serious Adverse Events Reported, and Other Significant Adverse Events Reported.

### Deaths

Three patients died during the study. None of the deaths were considered
related to the study treatment.

### Other serious adverse events

Table 3.7.2.7 summarizes the serious adverse events reported during the
study. The total number of subjects reporting one or more serious
adverse events was 24. All of the serious adverse events were considered
unlikely to be related to study treatment. There were no serious adverse
events involving the donor sites.

+-----------------------------------------------------+----+-----------+
| Table 3.7.2.7: Serious Adverse Events Reported      |    |           |
+=====================================================+====+===========+
| **Body System**                                     | *  | **%**     |
|                                                     | *n |           |
| > **Preferred Term**                                | ** |           |
+-----------------------------------------------------+----+-----------+
| **Application Site Disorders**                      |    |           |
+-----------------------------------------------------+----+-----------+
| Cellulitis                                          | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Autonomic Nervous System Disorders**              |    |           |
+-----------------------------------------------------+----+-----------+
| Hypotension                                         | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Body As A Whole -- General Disorders**            |    |           |
+-----------------------------------------------------+----+-----------+
| Multiple Organ Failure                              | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Scar                                                | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| **Centr & Periph Nervous System Disorders**         |    |           |
+-----------------------------------------------------+----+-----------+
| Brain Stem Disorder                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Convulsions                                         | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Neuropathy                                          | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Gastro-Intestinal System Disorders**              |    |           |
+-----------------------------------------------------+----+-----------+
| Achalasia Cardiae                                   | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Heart Rate And Rhythm Disorders**                 |    |           |
+-----------------------------------------------------+----+-----------+
| Cardiac Arrest                                      | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Musculo-Skeletal System Disorders**               |    |           |
+-----------------------------------------------------+----+-----------+
| Bone Development Abnormal                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Red Blood Cell Disorders**                        |    |           |
+-----------------------------------------------------+----+-----------+
| Anaemia                                             | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Resistance Mechanism Disorders**                  |    |           |
+-----------------------------------------------------+----+-----------+
| Healing Impaired                                    | 2  | 2.4       |
+-----------------------------------------------------+----+-----------+
| Infection Aggravated                                | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Sepsis                                              | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| **Respiratory System Disorders**                    |    |           |
+-----------------------------------------------------+----+-----------+
| Dyspnoea                                            | 4  | 4.9       |
+-----------------------------------------------------+----+-----------+
| Larynx Oedema                                       | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Pneumonia                                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Pneumothorax                                        | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Secondary Terms**                                 |    |           |
+-----------------------------------------------------+----+-----------+
| Ectropion                                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Skin And Appendages Disorders**                   |    |           |
+-----------------------------------------------------+----+-----------+
| Skin Malformation                                   | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| **Urinary System Disorders**                        |    |           |
+-----------------------------------------------------+----+-----------+
| Renal Failure Acute                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Vascular (Extracardiac) Disorders**               |    |           |
+-----------------------------------------------------+----+-----------+
| Haematoma                                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **White Cell And Res Disorders**                    |    |           |
+-----------------------------------------------------+----+-----------+
| Lymphoedema                                         | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| **Body System Uncategorized**                       |    |           |
+-----------------------------------------------------+----+-----------+
| Entropion/Ectrop Rep Nec                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Lid Reconst W Skin Graft                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Lid Reconstr W Graft Nec                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Tot Nasal Reconstruction                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Other Pleural Incision                              | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Ext Fix Dev-Metacar/Carp                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Remove Impltd Device Nos                            | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Rotator Cuff Repair                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Finger Amputation                                   | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Other Local Destruc Skin                            | 3  | 3.7       |
+-----------------------------------------------------+----+-----------+
| Skin Suture Nec                                     | 2  | 2.4       |
+-----------------------------------------------------+----+-----------+
| Full-Thick Skin Graft Nec                           | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Heterograft To Skin                                 | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| Relaxation of Scar                                  | 4  | 4.9       |
+-----------------------------------------------------+----+-----------+
| Skin Repair & Plastic Nec                           | 2  | 2.4       |
+-----------------------------------------------------+----+-----------+
| Rehabilitation Nec                                  | 1  | 1.2       |
+-----------------------------------------------------+----+-----------+
| n=Number of Patients                                |    |           |
+-----------------------------------------------------+----+-----------+

# 

# 3.8 Conclusions Drawn from the Studies

The preclinical safety studies demonstrate that the device is composed
of biocompatible components. The animal studies also demonstrate that
the collagen sponge component of the device is rapidly resorbed and does
not interfere with wound repair.

CCS wound dressing has demonstrated a positive benefit (100%
re-epithelialization) in wound healing when evaluated in clinical
investigations. With respect to human clinical investigations, CCS has
been used in the treatment of over 186 patients in the U.S. and
Australia.

## Safety

The adverse effects observed during clinical evaluations of CCS in
patients with donor sites, ~~EB, full and deep partial thickness burns,
venous ulcers and diabetic ulcers~~ include a total of ~~eight~~ deaths
and ~~71~~ non-fatal serious adverse events in ~~186~~ patients. As
judged by the treating investigator, none of these adverse events were
definitely related to CCS.

Although few adverse events attributable to CCS have been reported,
adverse events commonly associated with the treatment of acute and
chronic wounds include, but are not limited to:

Odor

Pain

Redness/erythema

Pruritis/itching

Cellulitis

Infection

Rash

Scarring

Clinical investigations to date have not revealed any significant
clinical manifestations of product-related immuological reactions. These
clinical data include treatment of over 150 patients (i.e., 28 burn
patients, 12 patients with chronic wounds from EB, 17 chronic venous
stasis ulcer patients, 7 patients with diabetic foot ulcers and 90
patients with donor sites). Sera drawn from the patients in US studies
revealed no antibody responses to bovine serum proteins. The sponsor has
not determined the impact of device application on patients' humoral or
cellular immune responses to the allogeneic human cellular components of
CCS, i.e., keratinocytes and fibroblasts.

## Efficacy

The mean healing time to 100% wound healing in a large multicentered
clinical evaluation of donor sites was significantly shorter for the
CCS-treated donor sites than for the control-treated sites. The mean
healing times reported for the three methods of measurement were: 1) 18
days for CCS compared to 22.4 days for the control by photographic
analysis; 2) 13.7 days for CCS compared to 19.3 days for the control by
planimetric analysis; and, 3) 13.2 days for CCS compared to 18.4 days
for the control according to the investigator's evaluation. Median time
to healing by Kaplan-Meier estimate was also significantly different
favoring CCS-treated donor sites.

Based on this study as well as other studies summarized in this summary,
CCS is effective as an interactive wound dressing in the management of
split thickness donor sites.

**3.9** **CDRH Decision**

10. **Approval Specifications**