Methyl 5-aminolevulinate hydrochloride, cream, 160 mg/g, 2 g tube, Metvix, July 2007
Public summary document for Methyl 5-aminolevulinate hydrochloride, cream, 160 mg/g, 2 g tube, Metvix, July 2007
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Public Summary Document
Product: Methyl 5-aminolevulinate hydrochloride, cream, 160 mg/g, 2 g tube, Metvix
Sponsor: Galderma Australia Pty Ltd
Date of PBAC Consideration: July 2007
1. Purpose of Application
The re-submission sought an authority required listing for the treatment of superficial Basal Cell Carcinoma (sBCC) in patients who cannot have surgery.
2. Background
At its November 2005 meeting, the PBAC rejected an application for an authority required listing for treatment of patients aged 18 years or older with primary sBCC or nodular basal cell carcinoma (nBCC) where surgery is inappropriate due to the risk of post-surgical morbidities or disfigurement. (See Public Summary Document for November 2005).
3. Registration Status
Methyl 5-aminolevulinate hydrochloride is registered by the TGA for:
- the treatment of thin or non-hyperkeratotic and non-pigmented actinic keratoses on the face and scalp when other registered therapies are unacceptable (April 2003).
- primary treatment of superficial and/or nodular basal cell carcinoma where surgery is considered inappropriate (July 2003).
- the treatment of biopsy-proven squamous cell carcinoma in situ (Bowen's disease), where surgery is considered inappropriate (November 2006).
4. Listing Requested and PBAC’s View
Authority Required
Treatment of superficial basal cell carcinoma (BCC) in patients who cannot have surgical
excision, cryotherapy, or curettage with diathermy. The lesion must be previously
untreated and the diagnosis confirmed by biopsy. For PBAC’s view, see Recommendation
and Reasons.
5. Clinical Place for the Proposed Therapy
Some superficial BCC lesions may be difficult to treat with current available therapies. Metvix provides an alternative therapy for patients who are not suitable for current non-medicinal therapies.
6. Comparator
Appropriately, the submission nominated imiquimod as the main comparator.
7. Clinical Trials
New trial data presented as pivotal evidence in the re-submission was from one head-to-head
non randomised study (Nikkels et al, 2005) of methyl 5-aminolevulinate used together
with photodynamic therapy (MAL-PDT) compared with imiquimod.
As supportive evidence, the re-submission presented three trials for MAL-PDT: one
randomised, multicentre, phase III trial of PDT with MAL cream 160mg/g in comparison
with cryotherapy in patients with primary superficial basal cell carcinoma (T304)
and two single arm non-comparative studies of MAL-PDT in sBCC (T310 and T205).
The re-submission also presented, as supportive evidence, three trials for imiquimod:
one double blind, randomised vehicle-controlled trial (Geisse J et al, 2004) and two
open-label single arm non comparative studies of imiquimod in sBCC (Gollnick H et
al, 2005 and Shumack S et al, 2004).
These trials had been published at the time of submission, as follows:
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
Primary comparative study |
||
|
Nikkels et al |
Photodynamic therapy and imiquimod immunotherapy for basal cell carcinomas - Open, multicentre non-randomised study of photodynamic therapy with MAL cream 160mg/g in comparisons with imiquimod in patients with nBCC and sBCC. |
Acta Clin Belg. 2005 Sep-Oct;60(5):227-34. |
|
Supportive trials/studies: MAL-PDT |
||
|
T304 |
||
|
Basset-Seguin N et al, 2005 |
MAL-PDT versus cryotherapy in primary superficial BCC: results of 48 month |
10th World Congress of Cancers of the Skin, Vienna [poster]. |
|
Basset-Seguin N et al, 2004 |
Photodynamic therapy using Metvix is as efficacious as cryotherapy in BCC, with better cosmetic results. |
Journal of the European Academy of Dermatology and Venereology; 18(S2):413 [abstract]. |
|
Basset-Seguin N et al, 2004 |
MAL-PDT is as effective as cryotherapy in superficial BCC, with better cosmetic |
International Skin Cancer Conference, Zurich. |
|
Basset-Seguin N et al, 2003 |
Photodynamic therapy using methyl aminolevulinate is as efficacious as |
61st Annual American Academy of Dermatology Meeting, San Francisco [poster abstract, P235]. |
|
Basset-Seguin N et al, 2003 |
Photodynamic therapy using methyl aminolevulinate is as efficacious as |
83rd Annual Meeting of British Association of Dermatologists, Brighton [poster abstract, P248]. |
|
Basset-Seguin N et al, 2001 |
Photodynamic therapy using Metvix is as efficacious as cryotherapy in BCC, with better cosmetic results. |
European Academy of Dermatology and Venereology, Munich [poster abstract]. |
|
Basset-Seguin N et al, 2001 |
Photodynamic therapy using Metvix is as efficacious as cryotherapy in BCC, with better cosmetic results. |
Journal European Academy of Dermatology and Venereology 15N(Suppl 2) [poster abstract, P226]. |
|
T310 |
||
|
Viniciullo C et al, 2005 |
Photodynamic therapy with topical methyl aminolevulinate for “difficult-to-treat” basal cell carcinoma. |
British Journal of Dermatology Vol 152 (pp 765-772). |
|
Viniciullo C et al, 2004 |
MAL-PDT in patients with difficult to treat basal cell carcinoma: results of an Australian multicentre study. |
Poster presented to the International Skin Cancer Conference, July 2004, Zurich. |
|
Viniciullo C et al, 2003 |
Photodynamic therapy using methyl aminolevulinate in patients with basal cell carcinoma. |
European Academy of Dermatology and Venereleogy Congress, Barcelona, [poster]. |
|
Viniciullo C et al, 2005 |
Photodynamic therapy with topical methyl aminolaevulinate for “difficult-to-treat” basal cell carcinoma. |
British Journal of Dermatology 2005; 152:765-772 |
|
T205 |
||
|
Horn M et al, 2003 |
Topical methyl aminolevulinate photodynamic therapy in patients with basal cell carcinoma prone to complications and poor cosmetic outcome with conventional therapy. |
British Journal of Dermatology |
|
Supportive trial/studies: imiquimod |
||
|
Geisse J et al, 2004 |
Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: Results from two phase III, randomised, vehicle-controlled studies. |
J Am Acad Dermatol 2004;50:722-733 |
|
Gollnick H et al, 2005 |
Recurrence rate of superficial basal cell carcinoma following successful treatment
with imiquimod 5% cream: interim 2-year results from an ongoing |
Eur J Dermatol 2005;15(5):374-381 |
|
Shumack S et al, 2004 |
5% Imiquimod Cream for the Treatment of Large Superficial Basal Cell Carcinoma |
Arch Dermatol 2004;140(10):1286-1287 |
8. Results of Trials
The results of the primary outcome for the trials/studies presented in the re-submission
are summarised in the tables below.
Results of the primary comparative study:
MAL-PDT versus imiquimod, percentage of patients with complete response at 12 weeks
post treatment
|
Trial |
MAL-PDT |
Imiquimod |
Difference |
|---|---|---|---|
|
Nikkels et al (2005) |
12/13 (92%) |
6/8 (75%) |
17.3%(-16.0%, 50.6%) |
The primary comparative study (Nikkels et al 2005) was not randomised. There were
very few numbers of cases in each arm of the study (13 patients treated with MAL-PDT
and eight patients treated with imiquimod) and the subjects enrolled into the study
appeared to be a selection of cases previously treated by the investigators. The study
report did not report any predefined statistical analyses of efficacy outcomes or
any predefined values.
Results of the supportive trial/studies: MAL-PDT
Proportion of patients with complete response at 3 months post treatment (reported
for all treated patients), and verified by biopsy when performed
|
Trial |
MAL-PDT |
Cryotherapy |
ARD |
RR |
|---|---|---|---|---|
|
T304+ |
54/60 (90%) |
52/58 (90%) |
0.00 |
1.00 |
|
T310 (single arm)*= |
82/102 (80%) |
NA |
NA |
NA |
|
T205 (single arm)*= |
61/85 (72%) |
NA |
NA |
NA |
* the re-submission presented results for studies T205 and T310 in terms of number
of sBCC lesions treated as a single patients can have a mixture of BCC lesions types
in these studies.
^ calculated in Revman (random effects) during the evaluation.
= reported for histologically confirmed complete response rate
For trial T304, the re-submission reported the number and proportion of complete responders,
expressed in terms of the numbers of lesions and the numbers of patients; results
were presented for the per protocol lesions/patients (primary analyses).
For studies T310 and T205, because patients with sBCC and nBCC were enrolled in the
studies, the re-submission presented efficacy outcomes in terms of the number of sBCC
lesions treated. These were not the primary outcomes evaluated in the studies; the
primary outcome was the percentage of patients with complete response at 3 months
post treatment.
Results of the supportive trial/studies: Imiquimod
Composite clearance rates (patient response) at 12 weeks post treatment
|
Trial |
Imiquimod |
Placebo |
ARD |
RR |
|---|---|---|---|---|
|
Geisse et al (2004) |
139/185 (75%) |
6/360a (2%) |
0.73 |
45.08 |
|
Gollinick et al (2005) |
163/182 (89.6%) |
NA |
NA |
NA |
|
Shumack et al (2004) |
83% |
NA |
NA |
NA |
a number of patients in combined placebo groups for the two dosages in the Geisse et
al (2004) trial.
^ calculated in Revman (random effects) during the evaluation
The results of the composite clearance rates (patient response) at 12 weeks post treatment
were reported for the supportive trial/studies of imiquimod on a per patient basis.
The re-submission presented new toxicity data from the non-randomised comparative
study of MAL-PDT versus imiquimod. The key results are presented below.
Local and non-local adverse events for primary comparative study: MAL-PDT versus imiquimod
reported at 6 months
|
Adverse events |
MAL-PDT |
IMIQUIMOD |
||||
|---|---|---|---|---|---|---|
|
Severity |
+ |
++ |
+++ |
+ |
++ |
+++ |
|
Erythema, oozing, ulceration and crusts |
NR |
NR |
NR |
0 |
2/8 (25) |
6/8 (75) |
|
Crusts |
2/13 (15) |
1/13 (8) |
NR |
NR |
NR |
NR |
|
Pain |
7/13 (54) |
NR |
NR |
NR |
NR |
NR |
|
No crust and no pain |
6/13 (46) |
NR |
NR |
NR |
NR |
NR |
Severity is graded as + minimal, ++ moderate, or +++ intense
For PBAC’s comments on these results, see Recommendation and Reasons.
9. Clinical Claim
The re-submission described MAL-PDT as being no worse than imiquimod in terms of effectiveness
and toxicity and exhibits at least equivalent or better safety profile and compliance
rate.
For PBAC’s view of this claim, see Recommendation and Reasons.
10. Economic Analysis
The re-submission provided a preliminary economic evaluation. On the assumption of
equal effectiveness of MAL-PDT and imiquimod for the requested PBS restrictions, the
re-submission compared the costs per treatment course of MAL-PDT versus imiquimod.
The re-submission assumed that a full course of methyl-5-aminolevulinate (2 g tube:
cream used for 2 treatments one week apart) was equivalent to a full course of imiquimod
(cream used 5 days per week for 6 weeks, the re-submission assumed 70% of patients
will use 24 sachets and 30% will use 30 sachets (as per the full course recommended
in the TGA-approved product information)).
The evaluation advised that the re-submission had sourced costs for GP, dermatologist
visits and biopsy from the 2004 Medicare Benefits Schedule, thus the costs used in
the estimation of the cost of MAL-PDT treatments and imiquimod treatments were likely
to be underestimated. For PBAC’s comments, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated that in Year 5 of listing the likely number of patients /year
would be in the range 10,000 – 50,000 and the financial cost/year to the PBS (not
excluding co-payments or subtract any savings in use of other drugs) to be < $10 million.
12. Recommendation and Reasons
The PBAC considered that, for consistency with the current imiquimod restriction,
any restriction for MAL-PDT should be amended to include the wording “The date of
the pathology report and name of the Approved Pathology Authority must be provided
at the time of application.” Further a NOTE stipulating “No applications for increased
maximum quantities and/or repeats will be authorised” should be included. The Committee
accepted that it was unnecessary to require that patients be immunocompetent, unlike
with imiquimod.
The PBAC questioned whether the patients enrolled in the trials/studies forming the
evidentiary basis of the re-submission were representative of those for whom PBS listing
of MAL-PDT was sought. Some trials/studies included patients with nBCC lesions, whereas
the requested PBS listing is only for sBCC; some trials/studies restricted patient
or lesions from participating in the study/trial because the lesions were of a size
outside those specified in the trial protocol, whereas the requested restriction does
not specify size of lesions able to be treated on PBS with MAL-PDT; some studies enrolled
patients with difficult to treat BCC, and who had lesions that had been previously
treated, whereas the requested PBS listing is for primary (previously untreated) sBCC
lesions.
In addition, in view of the low numbers in the only study carrying out a direct comparison
with imiquimod and the resulting wide confidence intervals, the PBAC considered that
this trial lacked scientific rigour and it was difficult to be confident about a conclusion
that MAL-PDT is no worse than imiquimod in terms of safety and efficacy.
Given the uncertainty over the clinical comparison, the cost-minimisation approach
was not considered to be justified. The costs of imiquimod were overestimated, as
the PBAC considered the assumption that 30% of patients would require a full course
of 30 applications with imiquimod to be unjustified. Further, the assumption that
only dermatologists prescribe imiquimod was unjustified.
The costs of MAL-PDT were considered to have been underestimated. There was uncertainty
about the re-submission’s assumptions that the costs of photoactivation, which occurs
three hours after the cream application, would be included in the cost of the GP or
dermatologist visit. There are currently no MBS item numbers for PDT associated with
MAL activation. The re-submission’s assumption that 25% of patients would receive
treatment with MAL-PDT via the GP and 75% via the dermatologist is not supported with
any evidence. Given the time between application and photoactivation of the MAL cream
is three hours, the re-submission’s assumption that patients will be charged only
once for two visits to the GP or dermatologist in one day was not substantiated.
The PBAC therefore rejected the submission because of uncertain comparative effectiveness
and uncertain cost effectiveness. The Committee acknowledged that MAL-PDT would provide
an alternative therapeutic option.
Recommendation
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be subsidised in Australia. It considers submissions in this context. A PBAC decision not to recommend listing or not to recommend changing a listing does not represent a final PBAC view about the merits of the medicine. A company can resubmit to the PBAC or seek independent review of the PBAC decision.
14. Sponsor’s Comment
The sponsor intends to work collaboratively with the PBAC to secure reimbursement
of Metvix.
