CLINICAL REVIEW MEMO

Subject: Ortec International, Inc. Composite Cultured Skin use in
management of split thickness donor sites in burn patients (G990063
pivotal study), clinical comment summary: P010016 and P010016 A1, 2, 3.

Composite Cultured Skin (CCS) is a bi-layer skin substitute that
consists of keratinocytes and fibroblasts derived by culture allograft
of cells from the foreskin of neonates born to pre-screened and
consenting mothers. The sponsor, Ortec International, Inc., has
submitted P010016, which includes G990063 pivotal study report. P010016
review identified issues, which the sponsor has addressed in P010016
amendments 1, 2, and 3.

Herein please find brief clinical comments on P010016, as well as
P010016 A1, 2, and 3.

# G990063 

# Pilot Study

G990063 pilot study design was a single-center, matched pair /
within-patient control, randomized study of the safety and preliminary
effectiveness CCS compared to a commercially available device, Biobrane,
in the management of split thickness donor sites in burn patients.
Specifically, two anatomically matched split thickness donor site wounds
per patient were assigned to be site 1 or site 2 per a standard
protocol. A randomization code was determined for each split thickness
donor site to designate treatment to the experimental (CCS) or control
(Biobrane) device. Fifteen to twenty patients were to be enrolled; eight
patients were enrolled. Based on analysis of data from five of seven
pilot study patients who completed the 28-day follow-up assessment
period, the observed median time to 100% re-epithelialization 21 days at
the Biobrane treated split thickness donor sites, and 12 days at the CCS
treated split thickness donor sites. Pivotal study designed was based on
pilot study design and outcomes.

Pivotal Study

G990063 pivotal study was a matched pair / within patient control,
multi-center study to demonstrate the superiority of CCS compared to
control, Biobrane -- L in

-   The safety and efficacy of CCS to facilitate timely wound closure of
    split thickness skin donor sites in burn patients, compared to
    control, Biobrane - L.

-   The functionality, durability of re-cropped skin serving as an
    autograft and time to complete (100% re-epithelialization) healing
    of the re-cropped and re-treated donor site in a subset of burn
    patients with massive surface area involvement who require
    re-harvesting as part of their complex wound and critical care
    management. (G990063s1, p15).

Inclusion Criteria

1.  Age \> /= 1 year

2.  Birth control for women of child bearing potential

3.  Total Body Surface Area (TBSA) burned = 10 = to 80%

4.  Burns due to thermal, chemical or friction injury

5.  Patients \>/= 3 years of age

-   Minimum total donor surface area (TDSA) = 72 to 90 cm2 (one
    investigational device of 36-45cm2 and one control site of an
    equivalent area);

-   Maximum TDSA = 288 to 360 cm2 (4 investigational devices of 144 to
    188 cm2 making up one test site and the control site of an
    equivalent area).

> Patients \< 3 years of age:

-   Minimum TDSA = 36 to 45 cm2, assuming use of one-half of an
    investigational device (18 to 22.5 cm2) and one control site of
    equivalent area;

-   Maximum TDSA = 144 to 180 cm2, assuming use of two investigational
    devices measuring 72 to 90 cm2 as one test site and the control site
    measuring the equivalent area; each device measuring 36cm2 (6 cm x
    6 cm) to 45 cm2 (6.7 cm x 6.7 cm).

6.  Donor sites:

-   To be in not previously harvested skin and not healed superficial
    partial thickness burn wounds.

-   To be on non-articulated surfaces, including back, buttocks and
    scalp.

7.  Split thickness donor sites to be

-   0.006 to 0.014 inch in depth

-   Both donor sites to be same depth

-   Treatment sites permitted to be slightly shallower: 0.004 -- 0.014
    inches if the sites were undergoing re-cropping.

8.  Informed consent

9.  Willingness to comply with protocol design

10. Life expectancy of at least six weeks after study entry.

Exclusion Criteria

1.  Sepsis with hemodynamic instability requiring pressor support or a
    microbiology report of positive blood cultures drawn within48 hours
    prior to surgery.

2.  Pregnant or lactating

3.  Severe inhalation injury requiring PEEP \> 20 and Fi02 \> 60% within
    12 hours prior to surgery.

4.  Trauma Scores:

> Injury Severity Score (ISS)

-   ISS \> 40 and age 15 to 49 years (y).

-   ISS \> 29 and age 45 to 65 y

-   ISS \> 25 and age \> 65y

> If age \< 15 y: Pediatric Trauma Score \</= 5 or pediatric Glasgow
> Coma Scale score \< 8

5.  Treatment with systemic corticosteroids during the 30 days prior to
    injury.

6.  Immunosuppressive, radiation or chemotherapy during the three months
    prior to injury.

7.  Previous participation in a trial for management of donor sites.

8.  Concurrent use of any investigational product on the burn sites.

9.  History of allergy or sensitivity to collagen material

10. History of insulin-dependent diabetes accompanied by glycosylated
    hemoglobin A1C \> 10%.

Donor Site Selection

Split thickness donor sites were to be selected according to the
Principal Investigator's routine surgical practice, guided by donor site
availability with attempt to identify to similar donor sites on each
patient. Discrete, contiguous, no-articulated sites were used.

Treatments

-   [Biobrane L]{.underline}

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-   Applied to the donor site, secured with staples, covered with gauze
    wraps.

-   Outer dressings generally removed after 24 -- 48 hours
    post-operatively

-   Attempts to remove Biobrane L from newly formed epidermis generally
    began between post-operative day 7 and 10.

-   Areas where Biobrane L remained adherent after soaking were
    considered non-epithelialized and open.

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-   [CCS]{.underline}

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-   Applied to donor site, secured with staples as per investigator
    discretion, covered with non-adherent, moisture retentive synthetic
    material, gauze wrap and Ace conforming bandage.

-   Outer dressing removed after 72 hours post-operatively and then
    every 48 to 72 hours, and backing irrigated with saline until
    post-operative day 7 when backing removal was attempted.

Follow-up

-   Screening, Day 0 (pre & post harvest), 3, 7, 14, 21, 28, week12, 24

Evaluation Parameters

-   Safety

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-   Adverse events

-   Scar outcome at 12 and 24 weeks by Vancouver Scar Scale:
    investigator evaluation

-   Scar outcome at 12 and 24 weeks by Hamilton Burn Scar Scale:
    photo-evaluation

-   Treated site pain, itching, infection

-   Donor site breakdown

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-   Effectiveness

## Primary

> Time to 100% wound healing by photography, evaluated in random order
> by three independent burn experts masked to study treatment.

## Secondary

-   Time to 100% wound healing by planimetry analyzed at a central
    laboratory masked to treatment assignment.

-   Time to 100% wound healing by investigator evaluation

-   Incidence of 100% wound healing

-   Time to re-cropping

# P010016 and P010016 A 2 & 3

Indication for Use: Ortec Inc., is seeking approval for CCS in the
management of split thickness donor site wounds in burn patients.
(P010016 A2, p1)

Sample size (prospective):

Seventy-five evaluable and 100 intent to treat patients; increased to 85
evaluable per amendment 3 (P010016V9, p 48).

Hypothesis:

-   Null: Time to healing in both arms are the same (P010016 amendment
    2, p204).

-   Alternative: Time to healing in both arms of the study are not the
    same (P010016 amendment 2, p204).

Study Power:

-   Prospective Power (EVL cohort, n = 84; 0.05 alpha): 80%(P010016
    amendment 2, p202)

Expected Time to 100% epithelialization with CCS: 17.5 days (P010016
amendment 2, p202)

Expected Time to 100% epithelialization with Biobrane-L: 27 days
(P010016 amendment 2, p202)

### Difference in Expected Time to 100% epithelialization: Biobrane minus CCS = 9.5days

-   Post-hoc Power (ITT cohort, n = 82; 0.05 2-sided alpha): 90%
    (P010016 amendment 2, p203)

Observed Time to 100% epithelialization with CCS: 18.0 days (P010016
amendment 3)

Observed Time to 100% epithelialization with Biobrane-L: 22.4 days
(P010016 amendment 3)

### Difference in Observed ITT cohort Time to 100% epithelialization: Biobrane minus CCS = 4.4 days

Post-hoc Power (PPT cohort, n = 72; 0.05 2-sided alpha): 85% (P010016
amendment 2, p203)

Observed Time to 100% epithelialization with CCS: 17.8 days (P010016
amendment 3)

Observed Time to 100% epithelialization with Biobrane-L: 22.1 days
(P010016 amendment 3)

### Difference in Observed PPP cohort Time to 100% epithelialization: Biobrane minus CCS = 4.3 days

Post-hoc Power (EVL cohort, n = 60; 0.05 2-sided alpha): 93% (P010016
amendment 3)

Observed Time to 100% epithelialization with CCS: 16.9 days (P010016
amendment 3)

Observed Time to 100% epithelialization with Biobrane-L: 22.3 days
(P010016 amendment 3)

### Difference in Observed EVL cohort Time to 100% epithelialization: Biobrane minus CCS = 5.4 days

The sponsor states that (P010016 amendment 2, p205) "at the time the
decision was reached to stop the study due to decreased enrollment rate,
approximately 90% of the patients achieved 100% healing. It was assumed
that the remaining patients would continue to 100% healing and that the
sample size of between 75 to 80 patients would be sufficient to achieve
statistical significance." The trial was stopped early, in May, 2000.

It is unclear when study blind to the sponsor was broken and analysis
undertaken.

Patient Accounting (Tables 11.1.1; C1, C2)

G990063 pivotal study was designed for 100 Intent to Treat (ITT)
patients with expectation of 25% loss to follow so as to provide a 75
patient Evaluable (EVL) cohort. Table C1 states that the study enrolled
an 82 patient ITT cohort and a 75 patient Evaluable (EVL) cohort. Table
C2 demonstrates that 60 patients completed study, are evaluable.
However, efficacy, is presented on the basis of a "per protocol"
population, which has 74 patients. The Per Protocol population is
defined as a subset of the Intent to Treat population which had no major
protocol violations, and sufficient planimetry data to determine time to
wound healing. This population is stated to have been defined by the
sponsor, internally, on November 13, 2000, at which time the sponsor
states that decision was also made to include seven steroid - treated
patients in the study. Steroid treated patient were to have been
excluded from study by study inclusion / exclusion criteria. The Per
Protocol Population is a retrospectively defined cohort: not addressed
in the original protocol or subsequent communications with FDA.

Patient Accounting

+---------------------------------------------------------+------------+
| N                                                       |            |
+---------------------------------------------------------+------------+
| Prospective sample size: ITT                            | 100        |
+---------------------------------------------------------+------------+
| Prospective sample size: EVL                            | 85         |
+---------------------------------------------------------+------------+
|                                                         |            |
+---------------------------------------------------------+------------+
| Enrolled: ITT                                           | 82         |
+---------------------------------------------------------+------------+
| Completed study: EVL                                    | 60         |
+---------------------------------------------------------+------------+
| Major Protocol Violations                               | 8          |
+---------------------------------------------------------+------------+
| Discontinued                                            | 22         |
+---------------------------------------------------------+------------+
| -   Adverse event                                       | 3          |
+---------------------------------------------------------+------------+
| -   Protocol violation                                  | 0          |
+---------------------------------------------------------+------------+
| -   Withdrew consent                                    | 0          |
+---------------------------------------------------------+------------+
| -   Lost to Follow-up                                   | 16         |
+---------------------------------------------------------+------------+
| -   Other                                               | 3          |
+---------------------------------------------------------+------------+
|                                                         |            |
+---------------------------------------------------------+------------+
| Efficacy, "Per Protocol"                                | 74         |
+---------------------------------------------------------+------------+
| Safety                                                  | 82         |
+---------------------------------------------------------+------------+

\*P010016v9, Tables 11.1.1; C1, C2

Demographics (P010016 v9 p52, 120 -- 123, and P010016 A3)

Data is presented for gender, and race, as well as mean age, height and
weight with standard deviation. Data is also presented for daily caloric
requirements, Injury Severity Score, Pediatric Trauma Score, and
Pediatric Glasgow Coma Score. Summary of donor site location, surface
area, and autograft thickness were presented for all patients and per
patient. Data represents pre-dominantly Caucasian male adults (age 15-65
years) with median height: 67 inches, weight: 160 pounds; median ISS:
11.0. Median Pediatric Trauma Score was 8.5; median Pediatric Glasgow
Coma Score was 15.0. Most (74%) donor sites treated with CCS or Biobrane
were located on the thigh. Appendix 1 to this review presents data.

Effectiveness

[Primary]{.underline}

> Time to 100% wound healing by photography, evaluated in random order
> by three independent burn experts masked to study treatment.

## Secondary

-   Time to 100% wound healing by planimetry analyzed at a central
    laboratory masked to treatment.

-   Time to 100% wound healing by investigator evaluation

-   Incidence of 100% wound healing

-   Time to re-cropping

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-   Time to 100% wound healing, Days

Methods of assessment for the ITT (Intent to Treat) and PPP (Per
Protocol Population censored at 32days) presented different mean and
median time to 100%, however, with consistent trend:

  ---------- ---------- ---------- ---------- ------------ ---------- ---------- ------------- ---------- ----------
             Clinical                         Planimetry                         Photography              

  ITT        CCS        Biobrane   p          CCS          Biobrane   p          CCS           Biobrane   p

  Median\*   12.0       16.0       \<0.0001   12.0         17.0       \<0.0001   15.0          22.0       0.0006

  Mean\*     13.2       18.4       \<0.0001   13.7         19.3       \<0.0001   18.0          22.4       \<0.0001

  PPP                                                                                                     

  Median\*   12.0       16.0       \<0.0001   12.0         16.0       \<0.0001   15.0          21.0       0.0009

  Mean\*     12.9       17.9       \<0.0001   13.4         18.7       \<0.0001   17.8          22.1       \<0.0001
  ---------- ---------- ---------- ---------- ------------ ---------- ---------- ------------- ---------- ----------

\*P010016, v9, p54-7.

Methods of assessment presented for the ITT population per investigator
(P010016, A2) demonstrate differences amongst investigators and between
methods that are greater than differences between treatment cohorts.
Trends, however, demonstrate time to 100% wound healing to range from no
difference between CCS and Biobrane, e.g., per investigators 4, 13 and
14 in median time to healing clinical assessment by investigator
(P010016, A2, p3) to shorter time to 100% wound healing with CCS than
Biobrane. No method or site / investigator mean or median assessment
demonstrated shorter time to 100% wound healing with Biobrane than with
CCS.

Median and mean with standard deviation for time to 100% from planimetry
by investigator:\*

  --------- -------- ------------------------- ---------------------------
                     ITT                       

            n        CCS                       Biobrane

  1         19       14.0; 14.2 (4.22)         26.0; 23.7 (7.59)

  2         1        10.0; 10.0 ( - )          14.0; 14.0 ( - )

  3         9        14.0; 15.3 (4.24)         28.0; 25.6 (6.88)

  4         16       11.0; 11.3 (3.04)         11.5; 12.8 (4.75)

  5         3        9.0; 16.0 (13.9)          11.0; 17.3 (12.7)

  6                  \-                        

  7         7        12.0; 11.3 (2.14)         15.0; 18.4 (8.12)

  8         9        11.0; 13.2 (7.24)         14.0; 18.2 (8.35)

  9                  \-                        \-

  10                 \-                        \-

  11                 \-                        \-

  12        2        \- ; 23.5 (12.0)          \- ; 23.5 (12.0)

  13        3        20.0;19.7 (9.50)          20.0; 22.0 (6.24)

  14        3        16.0; 15.7 (1.53)         16.0; 15.7 (1.53)

  15        10       11.0; 12.9 (7.26)         16.0; 18.2 (9.67)
  --------- -------- ------------------------- ---------------------------

\*P010016, v9, p147

Statistical assessment by the sponsor states that data is poolable
across centers. Please refer to FDA statistical review for FDA
statistical interpretation.

Time to 100% wound healing by photography, evaluated in random order by
three independent burn experts masked to study treatment: correlation
between masked assessors was requested well as per patient evaluation by
each assessor. Per patient evaluation per masked photo reviewer was not
provided. The sponsor has stated that two of the three agreeing photo
analyses were used in determining the photographic endpoint. Kappa
correlation coefficient for time to wound healing has been provided for
amongst investigators and methods and indicates acceptable correlation.
It is not stated, if kappa correlation was determined for all photo
evaluations by all three assessors, or for the two of three in closest
agreement.

  ------------------------------ ----------- -------------- --------------
                                 Kappa       95% LL         95% UL

  Photographic Reviewers:                                   

  PR1 / PR2                      0.8313      0.8000         0.8627

  PR1 / PR3                      0.8564      0.8272         0.8855

  PR2 / PR3                      0.8974      0.8723         0.9225

  Methods                                                   

  Photography / Planimetry       0.7324      0.6910         0.7739

  Photography / Investigator     0.7269      0.6854         0.7684

  Investigator / Planimetry      0.9563      0.9379         0.9748
  ------------------------------ ----------- -------------- --------------

The sponsor states that photography produced the greatest number of
healing times beyond 32 days for both CCS and Biobrane because if
photographs did not agree with the investigator assessment of 100% wound
healing the next follow-up was not until two to six months, resulting in
an artificially extended time (P010016, v9, p44).

Photo evaluators' report of incidence, mean, median and range of time to
100% wound healing (P010016 A3 and appendix 3 of this review) is higher
for incidence of 100% wound healing and shorter for mean time to 100%
wound healing for both CCS and Biobrane as performed by photo-evaluator
1 then by photo-evaluators 2 and 3. Final scores were determined by the
best of 2 of 3 evaluations per patient. Median time to 100% wound
healing, and relative difference between CCS and Biobrane are comparable
amongst the three evaluators.

Time to 100% wound healing covariate analysis was requested and response
provided (P010016 A2, p67-7) states that age, race and total body
surface are burned are significant co-variates for the ITT population
and variably for censored and uncensored per protocol populations.
Dexamethasone use, center, gender, trauma scores, and location of donor
site are not identified as significant co-variates. Please refer to FDA
statistical review for further interpretation of co-variate analysis.
Time to 100% wound healing for various subgroups, for ITT and PPP cohort
gender, age, and race, and by planimetry and photography for ITT cohort
age, TBSA, and wound area, without analyses of interaction, was
presented in e.g., tables: E1.5, E2.5, P9-A, B, C, and P11-A, B, C.

  --------------- ---- ---------- ---------- -------------- --------- ---------- ----------
  ITT (PPP)\*\*   n    Median,                              Mean,                
                       days                                 days                 

                       CCS        Biobrane   Difference\*   CCS       Biobrane   p

  Gender                                                                         

  Male            63   12.0       17.0       5.0 (4.0)      13.7      19.4       0.0002
                       (12.0)     (16.0)                                         

  Female          19   12.0       19.0       7.0 (4.0)      13.9      19.2       0.1083
                       (12.0)     (16.0)                                         

  Age                                                                            

  \<15 yo         22   12.0       14.0       2.0 (2.0)      12.2      15.3       0.1779
                       (12.0)     (14.0)                                         

  15 -- 65 yo     57   13.0       20.5       6.5 (3.5)      14.0      20.6       \<0.0001
                       (13.0)     (17.5)                                         

  \>65 yo         3    16.0       29.0       13.0 (13.0)    19.0      25.7       0.6547
                       (16.0)     (29.0)                                         

  Race                                                                           

  White           44   12.0       16.0       4.0 (3.0)      13.1      17.6       0.0195
                       (12.0)     (15.0)                                         

  Afro-American   20   14.0       23.0       9.0 (9.0)      15.0      22.4       0.0006
                       (14.0)     (23.0)                                         

  Other           18   12.0       16.0       4.0 (3.0)      13.9      20.1       0.1797
                       (12.0)     (15.0)                                         

  TBSA                                                                           

  \< 20%          21   12.0       14.0       2.0            11.8      13.6       0.3841

  20 -- 40%       47   12.0       21.0       9.0            14.1      20.5       \< 0.0001

  \>40%           14   15.0       25.0       10.0           18.0      15.4       0.0290

  Donor Area                                                                     

  \</= 45         20   12.0       15.0       3.0            11.9      17.3       0.0719

  \>45            62   13.0       18.0       5.0            14.3      20.0       0.0001
  --------------- ---- ---------- ---------- -------------- --------- ---------- ----------

\*Median days to 100% wound closure: CCS minus Biobrane \*\*data in ( )
are for the PPP cohort.

Differences in between genders, age groups, and races are noted,
however, inconclusive due to the small sample size of e.g. patients over
age 65 (n=3) and potential co-variate effects such as total body surface
area burned. From data provided, overall statistical significance
appears to driven by outcomes for patients who are male, more than 15
years old, with TBSA 20 --40%, and with donor area greater than 45cm2.
Per patient details are also provided in the four page summary chart in
Appendix 2 of this review. Please refer to FDA statistical review for
detailed interpretation of co-variate analysis presentation in P010016,
A3.

-   Incidence of 100% wound healing.

Incidence of 100% wound healing is presented in

-   Kaplan Meier Estimates of Percentage Patients with 100% wound
    closure from Planimetry

-   CCS: 94.07% patients healed by day 29, censored analysis.

-   Biobrane: 82.45% patients healed by day 32, censored analysis.

-   Donor sites with \> 32 days to healing (P010016, v9, p44)

  ----------------------------- --------------------- --------------------
                                CCS                   Biobrane

  Clinical                      1                     11

  Planimetry                    3                     11

  Photography                   7                     22
  ----------------------------- --------------------- --------------------

Incidence evaluated by photo evaluator 1 is higher than as determined by
photo evaluators 2 and 3 who are comparable. The difference between CCS
and Biobrane, however, is comparable amongst photo evaluators. (P016001
A3 and appendix 4 of this review).

-   Time to re-cropping

Mean and median time to readiness for re-cropping is reported in P010016
(V9, p151). Time to readiness for re-cropping from day of device
placement and day of 100% wound healing is reported in P010016 Table 13
and 14.

  ------------------------- -------- ------------------- ------------------
                            n        CCS                 Biobrane

  ITT\*                                                  

  Median                    82       14.0                21.0

  Mean                      82       15.9                20.8

  PPP\*\*                                                

  Median                             14.0                20.4

  Mean                               15.6                20.0

  \*\*\*From day of device                               
  placement                                              

  Median                    82       15                  21

  Mean                      82       18.01               43.05

  \*\*\*From day of 100%                                 
  healing                                                

  Median                    82       1                   1

  Mean                      82       3.82                17.14
  ------------------------- -------- ------------------- ------------------

\*P010016, V9, p151

\*\*P010016, V9, p152

\*\*\*All patients: P010016, A3, Tables 13 and 14.

Of the 82 enrolled patients, 3 CCS sites (patient 01-009; 08-005;
03-001) and one Biobrane site (patient 01-009) are reported to have been
re-cropped (P010016 A2, p156). Two of the CCS re-cropped sites received
CCS and each is reported to have healed by day9; however, the graft
recipient site for one patient (08-005) is stated to had not healed by
day 14 and no further follow-up is reported; and the graft recipient
site for the second patient is stated to have not been followed except
for report that the donor and recipient sites were healed at 24 weeks
and 6 months later. Patient 01-009 re-cropped sites were treated with
Beta Glucan Collagen dressing s and the re-cropped donor site graft
recipient site healing data was not captured. *The limited data
precludes conclusions; post-market study is warranted to assure
acceptable healing of recropped sites and take of grafts from re-cropped
sites.*

Safety

Adverse Events at Donor Sites: number (%)\*

  ---------------------------- --------------------- --------------------
                               CCS                   Biobrane

                               N = 82                N = 82

  Application site reaction    1 (1.2%)              1 (1.2%)

  Pain                         4 (4.9%)              4 (4.9%)

  Infection                    1 (1.2%)\*\*          1 (1.2%)\*\*

  Surgical site reaction       1 (1.2%)              1 (1.2%)

  Bullous eruption             0.00                  1 (1.2%)

  Pruritis                     4 (4.9%)              5 (6.1%)

  Pustular rash                1 (1.2%)              0.00
  ---------------------------- --------------------- --------------------

\*P010016 A2, p164

\*\*same patient:

> CCS site: rare gram negative bacilli; rare gram-positive cocci in
> pairs; treated with Bactroban; resolved
>
> Biobrane site: rare gram negative bacilli; treated with Bactroban;
> resolved.

The profile of adverse events at the donor sites includes events
considered to be mild -- moderate and is comparable for CCS and
Biobrane. No severe or life threatening adverse events are reported at
the donor sites. Systemic adverse events are listed (P010016 A2,
p160-163 and appendix 3 to this review), however, device relation is
precluded as all patients received both devices concurrently. Systemic
effects of CCS use are confounded by the within patient control.

The adverse event of pustular rash is stated (P010016 A2, p158) to have
occurred in a two year old male who received two 6 x 6 cm2 pieces of CCS
to cover a donor site on his right thigh, and noted by parents on day 26
after CCS placement (October, 1999). The investigator is said to have
attributed the rash to contact dermatitis from pressure garments being
worn for scar management, and treated the rash with Eucerin and
Bacitracin for one month, with rash resolution in without sequelae in
two months (December, 1999).

The number of patients with signs of infection, breakdown / blistering,
and itching are listed separately (P010016 v9, p69; as well as A3 Tables
4, 13 and 14). At this time, it is not clear how itching as a
non-adverse event and pruritis as an adverse event were distinguished.
Scar evaluation by the investigator was performed at 12 and 24 weeks
using the Vancouver Burn Scar Scale, and by three photo evaluators using
the Hamilton Burn Scar Score (P010016 v9, p67 -- 68 and summary tables;
P010016 A3 Tables 2, as well as appendix 3 to this review).

Data source and IIT cohort outcomes are briefly summarized:

-   Infection was recorded as present or absent, along with signs of
    infection which were evaluated as the presents or absence of
    purulence, warmth, malodor, erythema, tenderness to palpation,
    induration, swelling, and localized pain exceeding expected
    post-operative discomfort. If infection was present, whether or not
    culture was performed was recorded. Infection was reported in one
    patient. The number of patients with signs of infections is
    comparable and the difference is not associated with a difference in
    incidence of infection.

-   Breakdown was recorded as percentage of breakdown at treatment site.
    Breakdown is reported at 4 CCS and 8 Biobrane sites. Breakdown per
    elapsed study day is presented from day six through thirty three and
    demonstrates a different time profile for breakdown at CCS and
    Biobrane sites: breakdown at CCS sites was noted at days 10, 11 and
    13, while breakdown at Biobrane sites was noted at days 22, 28,
    and 33. Two incidences of breakdown at the CCS sites are noted to
    have occurred two days after 100% healing at the CCS treated site
    (P010016 A3 Table 13). Six incidences of breakdown at Biobrane sites
    were noted to have occurred at 4 to 20 days after 100% healing at
    the Biobrane treated site (P010016 A3 Table 14

-   Itching was recorded as absent, mild, moderate, or severe. Breakdown
    by age and for censored as well as uncensored, ITT and PPP cohorts
    (P010016 A3 and appendix 3 of this review), as well as per patient.
    Profiles are presented (P010016 A3 and appendix 3 of this review).

-   Pain was assessed with the Wong-Baker Faces pain rating scale for
    patients more than three years old and visual analog scale with
    numeric markings for intensity (0 to 10: 0, no pain; 5, moderate
    pain; 10, worse possible pain). Assessment is presented for various
    age groups and time periods

-   Scar assessment by Vancouver Burn Scar Score (score range = 0 -- 15)
    by investigators indicates clinically comparable scores for CCS and
    Biobrane treated sites at 12 weeks (CCS mean less than 1 point lower
    than Biobrane mean; medians equal: 2), and CCS treated sites' median
    (2 of 15) points lower than the Biobrane treated sites' median score
    (4 of 15). The clinical significance of the difference in median
    Vancouver Burn Scar Score at 24 weeks is not consistent with changes
    in the Hamilton Burn Scar Score. Hamilton Burn Scar Score assessment
    was performed by assessment of photographs taken at 12 and 24 weeks
    and randomly assessed by three independent photo evaluators.
    Photo-evaluator 1 assessed lower scores for CCS and Biobrane sites
    than photo evaluators 2 and 3 whose assessments were more clinically
    comparable. This trend was found for assessment of incidence and
    time to 100% wound healing. Overall Hamilton Burn Scar median scores
    were equal (Hamilton Burn Score = 2) for CCS and Biobrane treated
    sites at 24 weeks. As the unmasked (Vancouver / investigator) and
    masked (Hamilton / photo -- evaluator) burn scar scores while not
    consistent in trend, both demonstrated approximate scores, scar
    outcome at CCS and Biobrane treated sites is clinically comparable.

+------------------+---------------+-----------------+-----------------+
|                  | CCS           | Biobrane        | p               |
+------------------+---------------+-----------------+-----------------+
| Sign of          | 81 (98.9%)    | 79 (96.3%)      | 0.157           |
| Infection        |               |                 |                 |
|                  | 1 ( 1.2%)     | 3 (3.7%)        |                 |
| Absent           |               |                 |                 |
|                  | 82 (100%)     | 82 (100%)       |                 |
| Present          |               |                 |                 |
|                  |               |                 |                 |
| N evaluated      |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| Signs of         | 76 (95.0%)    | 71 (89.9%)      | 0.248           |
| breakdown /      |               |                 |                 |
| blister          | 4 ( 5.0%)     | 8 (10.1%)       |                 |
|                  |               |                 |                 |
| Absent           | 80 (100%)     | 79 (100%)       |                 |
|                  |               |                 |                 |
| Present          |               |                 |                 |
|                  |               |                 |                 |
| N evaluated      |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| Itching          | 22 (27.8%)    | 25 (31.3%)      | 0.414           |
|                  |               |                 |                 |
| None             | 29 (36.7%)    | 28 (35.0%)      |                 |
|                  |               |                 |                 |
| Mild             | 21 (26.6%)    | 21 (26.3%)      |                 |
|                  |               |                 |                 |
| Moderate         | 7 (8.9%)      | 6 ( 7.5%)       |                 |
|                  |               |                 |                 |
| Severe           | 79 (100%)     | 80 (100%)       |                 |
|                  |               |                 |                 |
| Total            |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| Mean Pain, age   | 1.4           | 1.8             |                 |
| \> 8             |               |                 |                 |
|                  | 1.7           | 1.8             |                 |
| Mean (of means)  |               |                 |                 |
|                  | 0 -- 9.0      | 0 -- 9.0        |                 |
| Standard         |               |                 |                 |
| Deviation        | 1             | 1.2             |                 |
|                  |               |                 |                 |
| Range            | 56            | 57              |                 |
|                  |               |                 |                 |
| Median (of       |               |                 |                 |
| means)           |               |                 |                 |
|                  |               |                 |                 |
| N, evaluated     |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| Vancouver Scar\* | 54            | 54              | 0.017           |
|                  |               |                 |                 |
| Week 12, n       | 2.26          | 3.07            | 0.002           |
|                  |               |                 |                 |
| Mean             | 2             | 2               |                 |
|                  |               |                 |                 |
| Median           | 55            | 56              |                 |
|                  |               |                 |                 |
| Week 24, n       | 2.56          | 3.79            |                 |
|                  |               |                 |                 |
| Mean             | 2             | 4               |                 |
|                  |               |                 |                 |
| Median           |               |                 |                 |
+------------------+---------------+-----------------+-----------------+
| Hamilton Scar    | 55            | 55              | 0.018           |
| Score\*\*        |               |                 |                 |
|                  | 3.89          | 4.95            | 0.020           |
| Week 12, n       |               |                 |                 |
|                  | 3             | 5               |                 |
| Mean             |               |                 |                 |
|                  | 48            | 50              |                 |
| Median           |               |                 |                 |
|                  | 2.46          | 3.5             |                 |
| Week 24, n       |               |                 |                 |
|                  | 2             | 2               |                 |
| Mean             |               |                 |                 |
|                  |               |                 |                 |
| Median           |               |                 |                 |
+------------------+---------------+-----------------+-----------------+

by investigator

\*\*by three photo evaluators

Conclusion

Ortec Inc. has presented outcomes of a matched pair / within patient
control, multi-center study to demonstrate the superiority of CCS
compared to control, Biobrane -- L in the safety and efficacy of CCS to
facilitate timely wound closure of split thickness skin donor sites in
burn patients, compared to control, Biobrane - L.

This study was also to assess the functionality, durability of
re-cropped skin serving as an autograft and time to complete (100%
re-epithelialization) healing of the re-cropped and re-treated donor
site in a subset of burn patients with massive surface area involvement
who require re-harvesting as part of their complex wound and critical
care management. However, of the 82 enrolled patients, only three
patients had 3 CCS sites (patient 01-009; 08-005; 03-001) re-cropped and
only one patient had a Biobrane site (patient 01-009) re-cropped. Of the
three re-cropped CCS sites only two re-cropped sites received CCS.