TABLE OF CONTENTS

## Executive Summary Tab 1

Appendix 1 -- Clinical Trials Tab 2

Appendix 2 -- Tables on Efficacy of Studies 307 & 308 Tab 3

Appendix 3 -- Flowchart for pivotal study design Tab 4

Appendix 4 -- Analysis of the sensitization potential by Tab 5

Methyl aminolevulinate cream vs. vehicle vs.

Aminolevulinic acid (ALA) vs. ALA vehicle

Appendix 5 -- Reference Article Tab 6

**Executive Summary**

**NDA 21-576**

**September 10, 2003 Advisory Committee**

Basal cell carcinoma (BCC) is one of the most common forms of skin
cancer worldwide. In the United States, almost a million people per year
are diagnosed with BCC. Excisional techniques (including Mohs'
micrographic surgery) are commonly used for treatment of BCC and allow
for histopathological confirmation of diagnosis and evaluation of tumor
involvement at the margins of excision.

This New Drug Application (NDA) is for the use of methyl aminolevulinate
hydrochloride cream 168 mg/g (MAL) with CureLight BroadBand Model
CureLight 01 lamp (emitting red light at 570 to 670 nm) for the
photodynamic therapy (MAL-PDT) treatment of primary nodular and
superficial basal cell carcinoma. Approval for primary superficial BCC
is contingent, in part, on a demonstration of safety and efficacy for
primary nodular BCC. The application included study reports describing
two vehicle controlled pivotal studies with 33 patients in each study
randomized to MAL who were followed for 6 months after treatment and
several open label studies in which some patients were followed for up
to 2 years after treatment (see Appendix 1). The dermal safety testing
of this drug product included evaluation for contact hypersensitivity.
Significant issues for discussion by the Advisory Committee include:

[A) Adequacy of Evidence for Effectiveness]{.underline}

PhotoCure demonstrated that MAL plus red light (MAL-PDT) is superior to
vehicle plus red light (VEH-PDT) in the treatment of nodular BCC in two
pivotal studies (Studies 307 and 308). Although the primary outcome
rates achieved after up to 4 treatments (2 treatment cycles) with
MAL-PDT and VEH-PDT were 76% and 34% for study 307 and 67% and 18% for
study 308 respectively, (as per Sponsor's analysis) two centers drove
the results in study 307 (see also FDA Biostatistical analysis --
Appendix 2). The study design for 307 and 308 was complex and relied on
several decision points (see Appendix 3). The primary endpoint relied on
histological evaluation at 6 months post treatment, i.e. bread-loafing
of specimen into sections not more than 3 mm thick. At least 6 to more
than 20 sections were examined for each case, depending on the size of
the lesion.

Lesion preparation may be a source of several significant concerns. The
high primary outcome rates achieved by the VEH-PDT arms in the two
studies may be due to lesion preparation (i.e., curettage). Differences
in lesion preparation from investigator to investigator may account for
very high inter-center variability (see Biostatistical analysis --
Appendix 2). Differences in lesion preparation may have been difficult
to avoid with the limited written instructions given to the trial
investigators regarding such preparation.

It was not possible to obtain recurrence data beyond 6 months after
treatment from these pivotal studies due to excision of the treatment
site for histological evaluation. Instead, recurrence was evaluated in
separate open-label studies. Fifty-two (52) subjects with nodular BCC
were followed for up to 24 months in Study 303, an open-label
multicenter trial conducted in Europe. These patients were compared to
49 subjects treated with surgical excision using 1 to 5 mm margins. \[It
was unclear if surgical margins were evaluated in the excised
specimens.\] Follow-up data at 12 and 24 months were evaluated for
recurrence. It was difficult to determine if follow-up determinations
were accurate for this study because the body charts showing tumor
location were not submitted. However, intent-to-treat (ITT) analysis
showed that 85% of the subjects receiving surgery had no clinical
recurrence by month 24 and only 67% of the subjects receiving MAL-PDT
had no clinical recurrence by month 24. No histological determination
for lack of recurrence was made. Twice as many subjects receiving
MAL-PDT were lost to follow-up as compared to those receiving surgery.

Study 205 was a single-arm, open-label, Phase 2 study that evaluated
both superficial and nodular BCC (overall BCC) for up to 24 months for
recurrence (94 patients were enrolled with 52 patients having a nodular
BCC component). Body charts were available for this study. Individual
lesions were analyzed for recurrence rather than by patient. At month 6,
the overall lesion clinical recurrence rate was 5%. None of the lesions
with a nodular component showed clinical recurrence; however,
superficial BCC treated with MAL-PDT had a recurrence rate of 10% at
month 6, and lesions on the trunk/neck had an 18% recurrence rate. At
month 12, the overall lesion recurrence rate was 9% with a notable 32%
recurrence rate for lesions located on the trunk or neck. At month 24 of
this study, the patient mean recurrence rate was 16% (95% confidence
interval of 6 to 26%). The clinical recurrence rate was higher (21%) for
superficial lesions treated with MAL-PDT than for nodular lesions (11%).
Overall, lesions treated with one PDT cycle (2 treatments) had a 13%
clinical recurrence rate, while lesions needing 2 PDT cycles (4
treatments) had an 18% recurrence rate by month 24. Overall, lesions
located on trunk/neck had higher clinical recurrence rates (36%) than
lesions located on face/scalp (9%). There was a positive correlation
between lesion diameter and recurrence rates (0 to 15 mm = 3%, 16 to 30
mm = 14%, and \>30 mm = 32%). Five year post-treatment recurrence data
is still pending from this study which began in 1999.

[B) Point Estimates of Efficacy and Comparison with Currently Available
Therapy]{.underline}

The following issues are relevant to evaluating the validity of the
point estimates for primary outcome in the MAL-PDT arm of studies 307
and 308:

1)  high variability from study site to study site, which may be due in
    part to variable lesion preparation and limited written description
    of lesion preparation instructions

2)  the post-treatment excision breadloafing used may miss microscopic
    nests of basal cell carcinoma

3)  the sensitivity of the histological examination of post-treatment
    excision at 6 months to provide an adequate estimate of long-term
    recurrence rates.

Drs. Rowe, Carroll, and Day published in the March 1989 issue of the
[Journal of Dermatologic Surgery and Oncology]{.underline}, a
meta-analysis review (Appendix 5) of 106 independent reports on
recurrence rates for treatment of primary basal cell carcinomas using
surgical excision, radiotherapy, cryosurgery, curettage and
electrodessication (ED&C), and Mohs micrographic surgery. The data for
this paper mixed results from lesions of varying size and location,
combining results from different observers. This paper amassed data on a
combined total of nearly 40,000 lesions. In this paper, the observed
five-year clinical lesion recurrence rates for BCC by treatment modality
were reported as follows: surgical excision 10.1%, radiotherapy 8.7%,
cryosurgery 7.5%, ED&C 7.7%, Mohs surgery 1.0%. The authors also stated
the following: "A good rule of thumb is that the 10-year recurrence rate
is double, or 2 times, that of the 2-year recurrence rate." This paper
provides a rationale for the need for long-term follow-up for basal cell
carcinoma.

[C) Contact Hypersensitivity to Drug Product]{.underline}

Contact hypersensitivity to drug product was demonstrated in 2
provocative sensitization studies. In the first study, a provocative
cumulative irritancy and sensitization (allergenicity) study was
conducted in 25 healthy adult subjects randomized and tested with MAL
and with vehicle cream. The first phase was stopped by the investigator
after 9 days rather than the usual 21 days because of the severity of
adverse skin reactions. After 9 days, 17 of the 25 subjects had contact
dermatitis. Five out of 25 had reactions consistent with topical
sensitization (allergic reaction).

In the second study (Appendix 4), 156 subjects were included. \[Due to
frequent skin reactions during induction, the investigator and PhotoCure
decided not to include more subjects\]. Fifty-eight of the 156 subjects
decided not to participate in the challenge (allergic reaction) phase of
the study. Fifty-eight of the 98 subjects proceeding to the challenge
phase allowed both MAL and aminolevulinic acid (ALA, an endogenous
protoporphyrin) to be tested. Forty subjects allowed only ALA to be
applied due to reactions with MAL during the initial phase. PhotoCure's
analysis of the sensitization potential by MAL revealed that 52% of the
58 subjects were regarded as positive with respect to contact
sensitization. Only 2% of the 98 subjects demonstrated contact
sensitization to vehicle. The Applicant concluded that the sensitization
and irritation are related to the drug substance and not to the vehicle.

In conclusion, PhotoCure's application for methyl aminolevulinate
hydrochloride cream, 168 mg/g, demonstrated a statistically significant
advantage of the product over the vehicle when used in conjunction with
lesion preparation (curettage) and the CureLight BroadBand Model
CureLight 01 lamp (emitting red light at 570 to 670 nm) for the
prespecified primary outcome measure in the photodynamic therapy (PDT)
of nodular and superficial basal cell carcinoma (BCC). The committee is
asked to consider the adequacy of the evidence for efficacy and
recurrence of BCC, the relative efficacy/non-recurrence as compared to
existing therapies, and the potential for and consequences of
sensitization of patients and practitioners and their staff with use of
this product.

[Questions for the Advisory Committee:]{.underline}

1\) PhotoCure assessed efficacy for the treatment of nodular BCC with
the following:

a.  6 month post-treatment by histology only (not clinical) in two
    pivotal studies (no follow-up available) with 66 patients on
    MAL-PDT.

b.  2 year clinical follow-up in open label studies in 86 patients.

Did PhotoCure adequately assess efficacy in the clinical studies?

2\) Has PhotoCure adequately demonstrated and described the lesion
preparation for use of this product?

3\) Is the level of efficacy adequate, given the efficacy of treatments
and products currently available for this indication?

4\) Has the safety profile for this product been adequately assessed?

5\) Is the contact sensitization rate acceptable?

6\) Has PhotoCure identified, and conducted sufficient studies in, an
appropriate patient population for the use of this product?

7\) Given the safety and efficacy information, does the Committee find a
favorable risk vs. benefit balance to support approval of this product?

8\) What additional studies are needed? Are these studies needed before
or after approval of the product?

9\) For future development of this and/or other drug products for this
indication, which measure(s) should be the key parameter(s) for
efficacy, e.g., clinical evaluation and/or histological clearing? at
what time point? recurrence rates? at what time point?

Appendix 1

Clinical Trials

+--------+-----+--------+----------+------------+--------------------+
| *      | **L | **Popu | **Study  | **Number   | **Curette-MAL-PDT  |
| *Study | oca | lation | Type**   | of         | and Comparator     |
| Nu     | tio | Stu    |          | Subjects   | Regimen (if not    |
| mber** | n** | died** |          | per Study  | vehicle            |
|        |     |        |          | Arm**      | controlled)**      |
+--------+-----+--------+----------+------------+--------------------+
| **     |     |        |          |            |                    |
| Vehicl |     |        |          |            |                    |
| e-Cont |     |        |          |            |                    |
| rolled |     |        |          |            |                    |
| Multi  |     |        |          |            |                    |
| center |     |        |          |            |                    |
| Stu    |     |        |          |            |                    |
| dies** |     |        |          |            |                    |
+--------+-----+--------+----------+------------+--------------------+
| PC     | USA | P      | Mult     | 33         | 2 treatment        |
| T      |     | rimary | icenter, | Curet      | sessions conducted |
| 307/00 |     | N      | doubl    | te-MAL-PDT | 7 days apart, if   |
|        |     | odular | e-blind, |            | partial response   |
| Dec.   |     | BCC    | ran      | 32         | at 3 months        |
| 2000   |     |        | domized, | Curet      | follow-up another  |
| to     |     |        | vehicle  | te-VEH-PDT | treatment cycle    |
| April  |     |        | co       |            | was given. 6       |
| 2002   |     |        | ntrolled |            | months after last  |
|        |     |        |          |            | PDT, all lesions   |
|        |     |        |          |            | were excised for   |
|        |     |        |          |            | histological       |
|        |     |        |          |            | evaluation.        |
+--------+-----+--------+----------+------------+--------------------+
| PC     | Aus | P      | Mult     | 33         | 2 treatment        |
| T      | tra | rimary | icenter, | Curet      | sessions conducted |
| 308/00 | lia | N      | doubl    | te-MAL-PDT | 7 days apart, if   |
|        |     | odular | e-blind, |            | partial response   |
| Oct.   |     | BCC    | ran      | 33         | at 3 months        |
| 2000   |     |        | domized, | Curet      | follow-up another  |
| to     |     |        | vehicle  | te-VEH-PDT | treatment cycle    |
| Sept.  |     |        | co       |            | was given. 6       |
| 2002   |     |        | ntrolled |            | months after last  |
|        |     |        |          |            | PDT, all lesions   |
|        |     |        |          |            | were excised for   |
|        |     |        |          |            | histological       |
|        |     |        |          |            | evaluation.        |
+--------+-----+--------+----------+------------+--------------------+
| *      |     |        |          |            |                    |
| *Open, |     |        |          |            |                    |
| Activ  |     |        |          |            |                    |
| e-Cont |     |        |          |            |                    |
| rolled |     |        |          |            |                    |
| Stu    |     |        |          |            |                    |
| dies** |     |        |          |            |                    |
+--------+-----+--------+----------+------------+--------------------+
| PC     | Eur | P      | Mult     | 52         | 2 treatment        |
| T      | ope | rimary | icenter, | Curet      | sessions conducted |
| 303/99 |     | N      | open,    | te-MAL-PDT | 7 days apart, if   |
|        |     | odular | ra       |            | partial response   |
| O      |     | BCC    | ndomized | 49         | at 3 months        |
| ngoing |     |        | vs.      | Surgical   | follow-up another  |
|        |     |        | surgical | Excision   | treatment cycle    |
| I      |     |        | excision |            | was given./or      |
| nterim |     |        |          |            |                    |
| Report |     |        |          |            | A single surgical  |
| In     |     |        |          |            | excision with      |
| itial: |     |        |          |            | margins from 1 to  |
| Apr.   |     |        |          |            | 5 mm.              |
| 2000   |     |        |          |            |                    |
|        |     |        |          |            |                    |
| 12     |     |        |          |            |                    |
| m:Apr. |     |        |          |            |                    |
| 2002   |     |        |          |            |                    |
|        |     |        |          |            |                    |
| 24m:   |     |        |          |            |                    |
| Nov.   |     |        |          |            |                    |
| 2002   |     |        |          |            |                    |
+--------+-----+--------+----------+------------+--------------------+
| PC     | Eur | P      | Mult     | 60         | 1 treatment        |
| T      | ope | rimary | icenter, | Curet      | session conducted, |
| 304/99 |     | Super  | open,    | te-MAL-PDT | if partial         |
|        |     | ficial | ra       |            | response at 3      |
| O      |     | BCC    | ndomized | 58         | months follow-up   |
| ngoing |     |        | vs.      | C          | another treatment  |
|        |     |        | cry      | ryotherapy | cycle was given    |
| I      |     |        | otherapy |            | consisting of 2    |
| nterim |     |        |          |            | treatment session  |
| Report |     |        |          |            | 7 days apart./or   |
| In     |     |        |          |            |                    |
| itial: |     |        |          |            | Min. 20 sec.       |
| May    |     |        |          |            | double freeze-thaw |
| 2002   |     |        |          |            | cycle with         |
|        |     |        |          |            | hand-held liquid   |
| 12m:   |     |        |          |            | nitrogen spray.    |
| Nov.   |     |        |          |            | Response           |
| 2002   |     |        |          |            | evaluation after 3 |
|        |     |        |          |            | months. If         |
| 24m:   |     |        |          |            | non-complete       |
| Nov.   |     |        |          |            | response at the 3- |
| 2002   |     |        |          |            | month evaluation,  |
|        |     |        |          |            | cryotherapy was    |
|        |     |        |          |            | repeated with      |
|        |     |        |          |            | final response     |
|        |     |        |          |            | evaluation 3       |
|        |     |        |          |            | months later (6    |
|        |     |        |          |            | months after the   |
|        |     |        |          |            | initial            |
|        |     |        |          |            | treatment).        |
+--------+-----+--------+----------+------------+--------------------+
| *      |     |        |          |            |                    |
| *Open, |     |        |          |            |                    |
| Non    |     |        |          |            |                    |
| -compa |     |        |          |            |                    |
| rative |     |        |          |            |                    |
| S      |     |        |          |            |                    |
| tudies |     |        |          |            |                    |
| in     |     |        |          |            |                    |
| Pati   |     |        |          |            |                    |
| ents** |     |        |          |            |                    |
+--------+-----+--------+----------+------------+--------------------+
| PC     | Eur | Super  | Mult     | 94         | 2 treatment        |
| T      | ope | ficial | icenter, | Curet      | sessions conducted |
| 205/98 |     | and    | open,    | te-MAL-PDT | 7 days apart, if   |
|        |     | n      | non-com  |            | partial response   |
| O      |     | odular | parative |            | at 3 months        |
| ngoing |     | BCC    |          |            | follow-up another  |
|        |     |        |          |            | treatment cycle    |
| I      |     |        |          |            | was given.         |
| nterim |     |        |          |            | Clinical complete  |
| Report |     |        |          |            | response verified  |
| In     |     |        |          |            | by histology from  |
| itial: |     |        |          |            | a punch biopsy or  |
| Dec.   |     |        |          |            | a surgical         |
| 2000   |     |        |          |            | procedure and a    |
|        |     |        |          |            | photograph.        |
| 12m:   |     |        |          |            |                    |
| Dec.   |     |        |          |            |                    |
| 2000   |     |        |          |            |                    |
|        |     |        |          |            |                    |
| 24m:   |     |        |          |            |                    |
| Jun.   |     |        |          |            |                    |
| 2002   |     |        |          |            |                    |
+--------+-----+--------+----------+------------+--------------------+
| PC     | Aus | Super  | Mult     | 102        | 2 treatment        |
| T      | tra | ficial | icenter, | Curet      | sessions conducted |
| 310/00 | lia | and    | open,    | te-MAL-PDT | 7 days apart, if   |
|        |     | n      | non-com  |            | partial response   |
| O      |     | odular | parative |            | at 3 months        |
| ngoing |     | BCC    |          |            | follow-up another  |
|        |     |        |          |            | treatment cycle    |
| I      |     |        |          |            | was given.         |
| nterim |     |        |          |            | Complete response  |
| Report |     |        |          |            | verified           |
| In     |     |        |          |            | histologically,    |
| itial: |     |        |          |            | with punch         |
| Jan.   |     |        |          |            | biopsies in a grid |
| 2002   |     |        |          |            | pattern for        |
|        |     |        |          |            | lesions with       |
| 12m:   |     |        |          |            | pre-treatment      |
| Sept.  |     |        |          |            | diameter \>10mm.   |
| 2002   |     |        |          |            |                    |
+--------+-----+--------+----------+------------+--------------------+

Appendix 2

Tables on Efficacy for Studies 307 & 308

Patients with Histological Complete Response -- Sponsor's Analysis

+-------------------+---------------------+----------------+----------+
| **Analyses**      | **Curette-MAL-PDT** | **Cur          | *        |
|                   |                     | ette-Veh-PDT** | *p-value |
|                   |                     |                | ^1^**    |
+-------------------+---------------------+----------------+----------+
| **Study 307**     | 25/33 (76%)         | 11/32 (34%)    | \< 0.001 |
|                   |                     |                |          |
| **ITT, n/N (%)**  | 24/31 (77%)         | 11/32 (34%)    | \< 0.001 |
|                   |                     |                |          |
| **PP, n/N (%)**   |                     |                |          |
+-------------------+---------------------+----------------+----------+
| **Study 308**     | 22/33 (67%)         | 6/33 (18%)     | \< 0.001 |
|                   |                     |                |          |
| **ITT, n/N (%)**  | 21/29 (72%)         | 6/32 (19%)     | \< 0.001 |
|                   |                     |                |          |
| **PP, n/N (%)**   |                     |                |          |
+-------------------+---------------------+----------------+----------+
| **^1^**           |                     |                |          |
| Cochra            |                     |                |          |
| n-Mantel-Haenszel |                     |                |          |
| test adjusting    |                     |                |          |
| for center.       |                     |                |          |
+-------------------+---------------------+----------------+----------+

+--------------------+------------------+--------------+--------------+
|                    | Curette-MAL-PDT  | Cur          | p-value      |
|                    |                  | ette-Veh-PDT | **^1^**      |
+--------------------+------------------+--------------+--------------+
| # Study 307        | 17/33 (51.5%)    | 5/32 (15.6%) | 0.003        |
|                    |                  |              |              |
| 1^st^ PDT cycle \* | 24/33 (73%)      | 8/32 (25%)   | \< 0.001     |
|                    |                  |              |              |
| Overall \*\*       |                  |              |              |
+--------------------+------------------+--------------+--------------+
| # Study 308        | 16/33 (48.5%)    | 3/33 (9.1%)  | \< 0.001     |
|                    |                  |              |              |
| 1^st^ PDT cycle \* | 21/33 (64%)      | 5/33 (15%)   | \< 0.001     |
|                    |                  |              |              |
| Overall \*\*       |                  |              |              |
+--------------------+------------------+--------------+--------------+
| **^1^**            |                  |              |              |
| Cochr              |                  |              |              |
| an-Mantel-Haenszel |                  |              |              |
| test adjusting for |                  |              |              |
| center.            |                  |              |              |
|                    |                  |              |              |
| \* One cycle = 2   |                  |              |              |
| treatments;        |                  |              |              |
| clinically clear   |                  |              |              |
| at month 3 and     |                  |              |              |
| histologically     |                  |              |              |
| clear at month 6.  |                  |              |              |
|                    |                  |              |              |
| \*\* For patients  |                  |              |              |
| treated with the   |                  |              |              |
| 1st PDT cycle,     |                  |              |              |
| clinically clear   |                  |              |              |
| at month 3 and     |                  |              |              |
| histologically     |                  |              |              |
| clear at month 6.  |                  |              |              |
| For patients       |                  |              |              |
| treated with 2 PDT |                  |              |              |
| cycles, clinically |                  |              |              |
| clear at month 6   |                  |              |              |
| and histologically |                  |              |              |
| clear at month 9.  |                  |              |              |
| Two PDT cycles (4  |                  |              |              |
| treatments) were   |                  |              |              |
| given to 10        |                  |              |              |
| patients on MAL    |                  |              |              |
| and 8 patients on  |                  |              |              |
| Veh in Study 307   |                  |              |              |
| and 5 patients on  |                  |              |              |
| MAL and 4 patients |                  |              |              |
| on Veh in Study    |                  |              |              |
| 308.               |                  |              |              |
+--------------------+------------------+--------------+--------------+

Lesions with Histological Complete Response -- Sponsor's Analysis

+---------------------------+----------------+--------------+---------+
| **Analyses**              | **Cur          | **Curet      | **      |
|                           | ette-MAL-PDT** | te-Veh-PDT** | p-value |
|                           |                |              | ^1^**   |
+---------------------------+----------------+--------------+---------+
| **Study 307**             | 32/41 (78%)    | 13/39 (33%)  | \<      |
|                           |                |              | 0.001   |
| **ITT, n/N (%)**          | 31/39 (79%)    | 13/37 (35%)  |         |
|                           |                |              | \<      |
| **PP, n/N (%)**           |                |              | 0.001   |
+---------------------------+----------------+--------------+---------+
| **Study 308**             | 23/34 (68%)    | 7/36 (19%)   | \<      |
|                           |                |              | 0.001   |
| **ITT, n/N (%)**          | 22/30 (73%)    | 7/33 (21%)   |         |
|                           |                |              | \<      |
| **PP, n/N (%)**           |                |              | 0.001   |
+---------------------------+----------------+--------------+---------+
| **^1^**                   |                |              |         |
| Cochran-Mantel-Haenszel   |                |              |         |
| test adjusting for        |                |              |         |
| center.                   |                |              |         |
+---------------------------+----------------+--------------+---------+

+--------------------+------------------+--------------+--------------+
|                    | Curette-MAL-PDT  | Cur          | p-value      |
|                    |                  | ette-Veh-PDT | **^1^**      |
+--------------------+------------------+--------------+--------------+
| # Study 307        | 19/41 (46%)      | 7/39 (18%)   | 0.007        |
|                    |                  |              |              |
| 1^st^ PDT cycle \* | 28/41 (68%)      | 10/39 (26%)  | \< 0.001     |
|                    |                  |              |              |
| Overall \*\*       |                  |              |              |
+--------------------+------------------+--------------+--------------+
| # Study 308        | 17/34 (50%)      | 4/36 (11%)   | \< 0.001     |
|                    |                  |              |              |
| 1^st^ PDT cycle \* | 22/34 (65%)      | 6/36 (17%)   | \< 0.001     |
|                    |                  |              |              |
| Overall \*\*       |                  |              |              |
+--------------------+------------------+--------------+--------------+
| **^1^**            |                  |              |              |
| Cochr              |                  |              |              |
| an-Mantel-Haenszel |                  |              |              |
| test adjusting for |                  |              |              |
| center.            |                  |              |              |
|                    |                  |              |              |
| \* One cycle = 2   |                  |              |              |
| PDT treatments;    |                  |              |              |
| clinically clear   |                  |              |              |
| at month 3 and     |                  |              |              |
| histologically     |                  |              |              |
| clear at month 6.  |                  |              |              |
|                    |                  |              |              |
| \*\* For lesions   |                  |              |              |
| treated with the   |                  |              |              |
| 1st PDT cycle,     |                  |              |              |
| clinically clear   |                  |              |              |
| at month 3 and     |                  |              |              |
| histologically     |                  |              |              |
| clear at month 6.  |                  |              |              |
| For lesions        |                  |              |              |
| treated with 2 PDT |                  |              |              |
| cycles, clinically |                  |              |              |
| clear at month 6   |                  |              |              |
| and histologically |                  |              |              |
| clear at month 9.  |                  |              |              |
| Two PDT cycles (4  |                  |              |              |
| treatments) were   |                  |              |              |
| given to 13        |                  |              |              |
| lesions on MAL and |                  |              |              |
| 9 lesions on Veh   |                  |              |              |
| in Study 307 and 5 |                  |              |              |
| lesions on MAL and |                  |              |              |
| 4 lesions on Veh   |                  |              |              |
| in Study 308.      |                  |              |              |
+--------------------+------------------+--------------+--------------+

![](media/image1.wmf)

**Lesion Complete Response Rate after the 1^st^ PDT Cycle**

by Center -- Studies 307 and 308

+---------+------------+-----------+---------+-----------+----------+
| **C     | **Study    |           | **C     | **Study   |          |
| enter** | 307**      |           | enter** | 308**     |          |
+---------+------------+-----------+---------+-----------+----------+
|         | **Curette  | *         |         | **Cur     | **Cure   |
|         | -MAL-PDT** | *Curette- |         | ette-MAL- | tte-Veh- |
|         |            | Veh-PDT** |         | PDT**     | PDT**    |
|         | **(n       |           |         |           |          |
|         | _bcc=41)** | **(n_     |         | **(n_     | **(n_b   |
|         |            | bcc=39)** |         | bcc=34)** | cc=36)** |
+---------+------------+-----------+---------+-----------+----------+
| **      | 2/7 (29%)  | 1/8 (13%) | **      | 1/2 (50%) | 0/3      |
| 30702** |            |           | 30801** |           |          |
+---------+------------+-----------+---------+-----------+----------+
| **      | 2/4 (50%)  | 0/2       | **      | 8/13      | 3/12     |
| 30703** |            |           | 30802** | (62%)     | (25%)    |
+---------+------------+-----------+---------+-----------+----------+
| **      | 0/7        | 1/7 (14%) | **      | NA        | 0/1      |
| 30704** |            |           | 30803** |           |          |
+---------+------------+-----------+---------+-----------+----------+
| **      | 1/2 (50%)  | 1/3 (33%) | **      | 2/2       | 0/3      |
| 30705** |            |           | 30804** | (100%)    |          |
+---------+------------+-----------+---------+-----------+----------+
| **      | 6/13 (46%) | 4/10      | **      | 3/4 (75%) | 1/5      |
| 30706** |            | (40%)     | 30805** |           | (20%)    |
+---------+------------+-----------+---------+-----------+----------+
| **      | 5/5 (100%) | 0/5       | **      | 3/8 (38%) | 0/7      |
| 30707** |            |           | 30806** |           |          |
+---------+------------+-----------+---------+-----------+----------+
| **      | 3/3 (100%) | 0/4       | **      | 0/5       | 0/5      |
| 30709** |            |           | 30807** |           |          |
+---------+------------+-----------+---------+-----------+----------+
| **      | 19/41      | 7/39      | **      | 17/34     | 4/36     |
| Total** | (46%)      | (18%)     | Total** | (50%)     | (11%)    |
+---------+------------+-----------+---------+-----------+----------+
| **B-D   | 0.025      |           | **B-D   | 0.560     |          |
| Test    |            |           | test    |           |          |
| ^1^**   |            |           | ^1^**   |           |          |
+---------+------------+-----------+---------+-----------+----------+
| **^1^** |            |           |         |           |          |
| B-D     |            |           |         |           |          |
| test    |            |           |         |           |          |
| for     |            |           |         |           |          |
| homo    |            |           |         |           |          |
| geneity |            |           |         |           |          |
| of      |            |           |         |           |          |
| re      |            |           |         |           |          |
| sponses |            |           |         |           |          |
| across  |            |           |         |           |          |
| c       |            |           |         |           |          |
| enters. |            |           |         |           |          |
+---------+------------+-----------+---------+-----------+----------+

**Sensitivity Analyses for Treatment-by-Center Interaction**

**Patient Response Rate After the 1^st^** PDT Cycle -- Study 307

+-------------+----------+-------------+------------+-------+-------+
| *           | **An     | **Curett    | **Curette  | **p-  | **B-D |
| *Endpoint** | alyses** | e-MAL-PDT** | -Veh-PDT** | value | test  |
|             |          |             |            | ^1^** | ^2^** |
+-------------+----------+-------------+------------+-------+-------+
| **Patient   | **All    | 17/33       | 5/32 (16%) | 0.003 | 0.045 |
| Complete    | c        | (51.5%)     |            |       |       |
| Response    | enters** |             |            |       |       |
| Rate**      |          |             |            |       |       |
+-------------+----------+-------------+------------+-------+-------+
|             | **Case   | 12.64/33    | 6.15/32    | 0.114 | 0.673 |
|             | (a)**    | (38%)       | (19%)      |       |       |
+-------------+----------+-------------+------------+-------+-------+
|             | **Case   | 10/26 (38%) | 5/24 (21%) | 0.204 | 0.427 |
|             | (b)**    |             |            |       |       |
+-------------+----------+-------------+------------+-------+-------+
| **Lesion    | **All    | 19/41 (46%) | 7/39 (18%) | 0.007 | 0.025 |
| Complete    | c        |             |            |       |       |
| Response    | enters** |             |            |       |       |
| Rate**      |          |             |            |       |       |
+-------------+----------+-------------+------------+-------+-------+
|             | **Case   | 13.80/41    | 8.80/39    | 0.331 | 0.805 |
|             | (a)**    | (34%)       | (23%)      |       |       |
+-------------+----------+-------------+------------+-------+-------+
|             | **Case   | 11/33 (33%) | 7/30 (23%) | 0.452 | 0.568 |
|             | (b)**    |             |            |       |       |
+-------------+----------+-------------+------------+-------+-------+
| **Case (a)  |          |             |            |       |       |
| = Impute    |          |             |            |       |       |
| centers     |          |             |            |       |       |
| with        |          |             |            |       |       |
| extreme     |          |             |            |       |       |
| efficacy    |          |             |            |       |       |
| results by  |          |             |            |       |       |
| the mean    |          |             |            |       |       |
| response of |          |             |            |       |       |
| the         |          |             |            |       |       |
| remaining   |          |             |            |       |       |
| centers**   |          |             |            |       |       |
|             |          |             |            |       |       |
| **Case (b)  |          |             |            |       |       |
| = Exclude   |          |             |            |       |       |
| centers     |          |             |            |       |       |
| with        |          |             |            |       |       |
| extreme     |          |             |            |       |       |
| efficacy    |          |             |            |       |       |
| results (2  |          |             |            |       |       |
| centers)**  |          |             |            |       |       |
|             |          |             |            |       |       |
| **^1^**     |          |             |            |       |       |
| C           |          |             |            |       |       |
| ochran-Mant |          |             |            |       |       |
| el-Haenszel |          |             |            |       |       |
| test        |          |             |            |       |       |
| adjusting   |          |             |            |       |       |
| for center. |          |             |            |       |       |
|             |          |             |            |       |       |
| **^2^** B-D |          |             |            |       |       |
| test is for |          |             |            |       |       |
| homogeneity |          |             |            |       |       |
| of          |          |             |            |       |       |
| responses   |          |             |            |       |       |
| across      |          |             |            |       |       |
| centers.    |          |             |            |       |       |
+-------------+----------+-------------+------------+-------+-------+

Appendix 3

![](media/image2.wmf){width="5.998611111111111in"
height="3.5944444444444446in"}Flowchart for pivotal study design

**Complete Response** = disappearance of lesions - excision at 6-month
for histology

**Partial Response** = lesion decreased by [\>]{.underline} 50%) -2nd
PDT cycle and excision at 9-month for histology

**No Response** or Progression = lesion decreased by \< 50% or lesion
increased by \> 20% - excision at 3-month

Appendix 4

Analysis of the sensitization potential by Methyl aminolevulinate cream
vs. vehicle vs. Aminolevulinic acid (ALA) vs. ALA vehicle

  --------------- ------------------ --------------- ---- -------------- ---- --------------- ----- ------------- ----
  **Compound**    **Number of        **Contact                                                                    
                  Subjects**         Sensitization                                                                
                                     Score**                                                                      

                                     **Positive**         **Negative**        **Equivocal**         **Missing**   

                  N                  n               \%   N              \%   n               \%    n             \%

  MAL Cream       58                 30              52   24             41   3               5     1             2

  Vehicle for MAL 58                 1               2    55             95   1               2     1             2

  ALA             98                 0               0    94             96   2               2     2             2

  ALA vehicle     98                 2               2    94             96   0               0     2             2
  --------------- ------------------ --------------- ---- -------------- ---- --------------- ----- ------------- ----