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 (
Appendix
5 – Reference Article Tab
6
Executive
Summary
NDA 21-576
Basal cell carcinoma (BCC) is one of
the most common forms of skin cancer worldwide.
In the
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
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
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
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, 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
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:
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
|
Study Number |
Location |
Population Studied |
Study Type |
Number of Subjects per
Study Arm |
Curette-MAL-PDT and
Comparator Regimen (if not vehicle controlled) |
|
Vehicle-Controlled
Multicenter Studies |
|||||
|
PC
T307/00 Dec.
2000 to April 2002 |
USA |
Primary Nodular BCC |
Multicenter,
double-blind, randomized, vehicle controlled |
33
Curette-MAL-PDT 32
Curette-VEH-PDT |
2
treatment sessions conducted 7 days apart, if partial response at 3 months
follow-up another treatment cycle was given.
6 months after last PDT, all lesions were excised for histological
evaluation. |
|
PC
T308/00 Oct. 2000 to Sept. 2002 |
Australia |
Primary Nodular BCC |
Multicenter, double-blind, randomized, vehicle controlled |
33
Curette-MAL-PDT 33 Curette-VEH-PDT |
2 treatment sessions conducted 7 days apart, if partial response at 3 months follow-up another treatment cycle was given. 6 months after last PDT, all lesions were excised for histological evaluation. |
|
Open,
Active-Controlled Studies |
|||||
|
PC
T303/99 Ongoing Interim
Report Initial: Apr. 2000 12m:Apr.
2002 24m: Nov. 2002 |
Europe |
Primary Nodular BCC |
Multicenter, open, randomized vs. surgical excision |
52
Curette-MAL-PDT 49 Surgical Excision |
2 treatment sessions conducted 7 days apart, if partial response at 3 months follow-up another treatment cycle was given./or A
single surgical excision with margins from 1 to 5 mm. |
|
PC
T304/99 Ongoing Interim
Report Initial: May 2002 12m:
Nov. 2002 24m: Nov. 2002 |
Europe |
Primary Superficial BCC |
Multicenter, open, randomized vs. cryotherapy |
60
Curette-MAL-PDT 58 Cryotherapy |
1 treatment session conducted, if partial response at 3 months follow-up another treatment cycle was given consisting of 2 treatment session 7 days apart./or Min. 20 sec. double freeze-thaw cycle with hand-held liquid nitrogen spray. Response evaluation after 3 months. If non-complete response at the 3- month evaluation, cryotherapy was repeated with final response evaluation 3 months later (6 months after the initial treatment). |
|
Open, Non-comparative
Studies in Patients |
|||||
|
PC
T205/98 Ongoing Interim
Report Initial: Dec. 2000 12m:
Dec. 2000 24m: Jun. 2002 |
Europe |
Superficial and nodular BCC |
Multicenter,
open, non-comparative |
94 Curette-MAL-PDT |
2
treatment sessions conducted 7 days apart, if partial response at 3 months
follow-up another treatment cycle was given. Clinical complete response verified by histology from a punch biopsy or
a surgical procedure and a photograph.
|
|
PC
T310/00 Ongoing Interim
Report Initial: Jan. 2002 12m:
Sept. 2002 |
Australia |
Superficial and nodular BCC |
Multicenter,
open, non-comparative |
102
Curette-MAL-PDT |
2
treatment sessions conducted 7 days apart, if partial response at 3 months
follow-up another treatment cycle was given. Complete response verified histologically, with punch biopsies in a grid
pattern for lesions with pre-treatment diameter >10mm. |
Appendix 2
Tables
on Efficacy for Studies 307 & 308
Patients with
Histological Complete Response – Sponsor’s Analysis
|
Analyses |
Curette-MAL-PDT |
Curette-Veh-PDT |
p-value 1 |
|
Study 307 ITT, n/N (%) PP, n/N (%) |
25/33
(76%) 24/31
(77%) |
11/32 (34%) 11/32 (34%) |
< 0.001 <
0.001 |
|
Study 308 ITT, n/N (%) PP, n/N (%) |
22/33 (67%) 21/29 (72%) |
6/33
(18%) 6/32
(19%) |
< 0.001 <
0.001 |
|
1 Cochran-Mantel-Haenszel
test adjusting for center. |
|||
Patient Response – FDA Analysis
|
|
Curette-MAL-PDT |
Curette-Veh-PDT |
p-value
1 |
Study 307
1st PDT cycle * Overall ** |
17/33
(51.5%) 24/33
(73%) |
5/32
(15.6%) 8/32
(25%) |
0.003 <
0.001 |
Study 308
1st PDT cycle * Overall ** |
16/33
(48.5%) 21/33
(64%) |
3/33
(9.1%) 5/33
(15%) |
<
0.001 <
0.001 |
|
1
Cochran-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 |
Curette-MAL-PDT |
Curette-Veh-PDT |
p-value 1 |
|
Study 307 ITT, n/N (%) PP, n/N (%) |
32/41
(78%) 31/39
(79%) |
13/39 (33%) 13/37 (35%) |
< 0.001 <
0.001 |
|
Study 308 ITT, n/N (%) PP, n/N (%) |
23/34 (68%) 22/30 (73%) |
7/36
(19%) 7/33
(21%) |
< 0.001 <
0.001 |
|
1 Cochran-Mantel-Haenszel
test adjusting for center. |
|||
Lesion Response – FDA Analysis
|
|
Curette-MAL-PDT |
Curette-Veh-PDT |
p-value
1 |
Study 307
1st PDT cycle * Overall ** |
19/41
(46%) 28/41
(68%) |
7/39
(18%) 10/39
(26%) |
0.007 <
0.001 |
Study 308
1st PDT cycle * Overall ** |
17/34
(50%) 22/34
(65%) |
4/36
(11%) 6/36
(17%) |
<
0.001 <
0.001 |
|
1
Cochran-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. |
|||
Lesion Complete Response Rate after the 1st PDT Cycle
by Center – Studies 307 and 308
|
Center |
Study 307 |
Center |
Study 308 |
||
|
Curette-MAL-PDT (n_bcc=41) |
Curette-Veh-PDT (n_bcc=39) |
Curette-MAL- PDT (n_bcc=34) |
Curette-Veh- PDT (n_bcc=36) |
||
|
30702 |
2/7
(29%) |
1/8
(13%) |
30801 |
1/2
(50%) |
0/3 |
|
30703 |
2/4
(50%) |
0/2 |
30802 |
8/13
(62%) |
3/12
(25%) |
|
30704 |
0/7 |
1/7
(14%) |
30803 |
NA |
0/1 |
|
30705 |
1/2
(50%) |
1/3
(33%) |
30804 |
2/2
(100%) |
0/3 |
|
30706 |
6/13
(46%) |
4/10
(40%) |
30805 |
3/4
(75%) |
1/5
(20%) |
|
30707 |
5/5
(100%) |
0/5 |
30806 |
3/8
(38%) |
0/7 |
|
30709 |
3/3
(100%) |
0/4 |
30807 |
0/5 |
0/5 |
|
Total |
19/41
(46%) |
7/39
(18%) |
Total |
17/34
(50%) |
4/36
(11%) |
|
B-D Test 1 |
0.025 |
B-D test 1 |
0.560 |
||
|
1
B-D
test for homogeneity of responses across centers. |
|||||
Sensitivity
Analyses for Treatment-by-Center Interaction
Patient Response
Rate After the 1st PDT Cycle – Study 307
|
Endpoint |
Analyses |
Curette-MAL-PDT |
Curette-Veh-PDT |
p-value1 |
B-D test2 |
|
Patient
Complete Response Rate |
All centers |
17/33 (51.5%) |
5/32 (16%) |
0.003 |
0.045 |
|
Case (a) |
12.64/33 (38%) |
6.15/32 (19%) |
0.114 |
0.673 |
|
|
Case (b) |
10/26 (38%) |
5/24 (21%) |
0.204 |
0.427 |
|
|
Lesion
Complete Response Rate |
All centers |
19/41 (46%) |
7/39 (18%) |
0.007 |
0.025 |
|
Case (a) |
13.80/41 (34%) |
8.80/39 (23%) |
0.331 |
0.805 |
|
|
Case (b) |
11/33 (33%) |
7/30 (23%) |
0.452 |
0.568 |
|
|
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 Cochran-Mantel-Haenszel
test adjusting for center. 2 B-D test is for homogeneity
of responses across centers. |
|||||
Appendix 3
Flowchart for pivotal study
design
Complete
Response = disappearance of lesions - excision at 6-month for histology
Partial
Response = lesion decreased by > 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 Subjects |
Contact 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 |