Methyl 5-aminolevulinate hydrochloride, cream, 160 mg/g, 2 g tube, Metvix, March 2008
Public summary document for Methyl 5-aminolevulinate hydrochloride, cream, 160 mg/g, 2 g tube, Metvix, March 2008
Page last updated: 04 July 2008
Public Summary Documents
Product: Methyl 5-aminolevulinate hydrochloride, cream, 160 mg/g, 2 g tube, Metvix
Sponsor: Galderma Australia Pty Ltd
Date of PBAC Consideration: March 2008
1. Purpose of Application
The submission sought a Section 85 Authority Required listing for the treatment of superficial Basal Cell Carcinoma (sBCC) in patients who cannot have surgery.
2. Background
At the 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. The PBAC rejected the submission because of the inappropriate
restriction, the trials were not representative of those for whom PBS listing was
sought and the primary outcome of the trial showed methyl aminolevulinate to be inferior
to surgery, and because of uncertain and inadequately demonstrated cost-effectiveness.
At the July 2007 meeting, the PBAC rejected a submission for an Authority Required
listing for treatment of sBCC in patients who cannot have surgery because of uncertain
comparative effectiveness and uncertain cost effectiveness.
3. Registration Status
Methyl 5-aminolevulinate hydrochloride is TGA registered for:
- 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)
- 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. The date of the pathology report
and name of the Approved Pathology authority must be provided at the time of application.
The wording as proposed by the Restrictions Working Group was:
Authority required
Treatment of biopsy confirmed primary (previously untreated with the sole exception
of lesions treated with methyl aminolevulinate photodynamic therapy in the preceding
3 months) superficial basal cell carcinoma (sBCC) in a patients for whom surgical
excision, cryotherapy, or curettage with diathermy are inappropriate and topical drug
therapy is required. The date of the pathology report and name of the Approved Pathology
Authority must be provided at the time of application.
NOTE:
No applications for increased maximum quantities and/or repeats will be authorised.
Treatment of recurrent (previously treated) lesions will not be authorised.
See Recommendation and Reasons for PBAC’s view.
5. Clinical Place for the Proposed Therapy
Metvix would provide an alternative therapy for the treatment of superficial basal cell carcinomas in patients where current non-medicinal therapies are inappropriate.
6. Comparator
The submission nominates imiquimod as the main comparator. The PBAC accepted that this was appropriate.
7. Clinical Trials
The re-submission presented new trial data, in addition to the data presented in the
previous re-submission. The re-submission presented a comparison of methyl aminolevulinate
photodynamic therapy (MAL-PDT) versus standard care, imiquimod versus standard care
and an indirect comparison of MAL-PDT versus imiquimod.
The re-submission presented a randomised controlled trial of MAL-PDT versus cryotherapy
in patients with “high risk” basal cell carcinoma and five non-randomised single arm
studies of MAL-PDT in patients with basal cell carcinomas. Only the randomised trial
specifically enrolled patients with superficial BCC (sBCC). However, where studies
enrolled patients with BCC, the re-submission only presented results for the sub-group
of patients with sBCC.
The re-submission presented the results of three randomised trials comparing imiquimod
versus vehicle and five non-randomised studies of imiquimod. Two randomised trials
and three non-randomised studies specifically enrolled patients with sBCC and one
randomised trial and two studies enrolled patients with basal cell carcinoma. In trials/studies
that enrolled patients with BCC, the re-submission only presented results for the
sub-group of patients with sBCC.
The Nikkels et al. (2005) study was presented as the pivotal evidence in the previous
re-submission, and is presented as supportive evidence in the current re-submission.
Studies published at the time of the submission are summarised in the table below.
|
Trial/First author |
Protocol title |
Publication citation |
|---|---|---|
|
MAL-PDT trials/studies |
||
|
T307 |
A multicentre, phase III, double blind study of photodynamic therapy (PDT) with Metvix 160 mg/g cream in comparison to PDT with placebo cream in patients with primary nodular basal cell carcinoma. |
19/07/02 |
|
Tope W et al, 2003 |
Randomized prospective comparison of topical methyl aminolevulinate photodynamic therapy versus placebo photodynamic therapy in nodular basal cell carcinoma. |
9th World Congress on Cancers of the Skin, May 2003, Sevilla [oral presentation] |
|
Tope WD et al, 2004 |
Comparison of topical methyl aminolevulinate photodynamic therapy versus placebo photodynamic therapy in nodular BCC. |
Journal of the European Academy of Dermatology and Venereology;18(S2):413 [abstract]. |
|
Tope WD et al, 2004 |
Comparison of topical methyl aminolevulinate photodynamic therapy versus placebo photodynamic therapy in nodular basal cell carcinoma: results of a North American study. |
International Skin Cancer Conference, Zurich [poster]. |
|
T308 |
A multi-centre, phase III, double-blind study of photodynamic therapy (PDT) with Metvix 160mg/g cream in comparison to PDT with placebo cream in patients with primary nodular basal cell carcinoma. |
27/11/02 |
|
Foley P et al, 2004 |
MALPDT or placebo cream in nodular basal cell carcinoma: results of an Australian double blind randomized multi-centre study. |
4th Euro PDT Meeting, Stirling Scotland [poster]. |
|
Foley P et al, 2004 |
MALPDT or placebo cream in nodular basal cell carcinoma: results of an Australian double-blind randomized multi-centre study. |
International Skin Cancer Conference, Zurich [poster]. |
|
Foley P et al, 2003 |
A phase III randomized study comparing photodynamic therapy (PDT) using methyl aminolevulinate or placebo cream in nodular basal cell carcinoma (NBCC) |
European Academy of Dermatology and Venereology Congress, Barcelona [poster]. |
|
Soler AM et al, 2001 |
A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevuinate-based photodynamic therapy alone and with prior curettage. |
Journal of Dermatology 145: 146-471. |
|
Surrenti T et al, 2007 |
An open-label trial to evaluate efficacy, safety, tolerability and cosmetic outcome of MAL-PDT in patients with superficial and nodular BCCs. |
European Journal of Dermatology 17 (5): 412-5. |
|
Caekelbergh K & |
Treatment of actinic keratosis and basal cell carcinoma with METVIX (MAL-PDT) in real life practice: a cost of illness and model validation study. |
Value in Health; |
|
Caekelbergh K & |
Study report “Observational study regarding the use of Metvix (MALPDT) in real life practice in Actinic Keratosis and Basal Cell Carcinoma” |
September 05 2006 Version No. 5.0 |
|
Imiquimod trials/studies |
||
|
Sterry W et al, 2002 |
Imiquimod 5% cream for the treatment of superficial and nodular basal cell carcinoma: randomised studies comparing low frequency dosing with and without occlusion. |
British Journal of Dermatology, 147:1227-1236 |
|
Marks R et al, 2001 |
Imiquimod 5% cream in the treatment of superficial basal cell carcinoma: Results of a multi-center 6- week dose-response trial. |
J Am Acad Dermatol, 44: 807-813. |
|
Peris K et al, 2005 |
Imiquimod Treatment of Superficial and Nodular Basal Cell Carcinoma: 12- Week Open-Label Trial. |
Dermatol Surg, 31: 318-323. |
|
Vidal D et al, 2004 |
Open study of the efficacy and mechanism of action of topical imiquimod in basal cell carcinoma. |
Clin Exp Dermatol, 29: 518-525 |
|
Geisse J et al, 2002 |
Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: A double-blind, randomised, vehicle-controlled study. |
Journal American Academy of Dermatol, 47: 390-398. |
8. Results of Trials
The key results of the additional MAL-PDT and imiquimod studies presented in the re-submission
are summarised in the table below.
Results of patient response rates in the additional MAL-PDT/imiquimod trials/studies
presented in the re-submission
|
Trial/study |
MAL-PDT/ imiquimod |
Placebo |
|---|---|---|
|
MAL-PDT |
||
|
Soler et al, 2001 |
NR |
NA |
|
Surrenti et al, 2007 |
NR |
NA |
|
Caekelbergh et al, 2006 |
88.6%a |
NA |
|
Imiquimod |
||
|
Geisse et al, 2002b |
5x/week: 21/26 (80.8) |
6/32 (18.8) |
|
Marks et al, 2001b |
3x/week: 23/33 (70) |
NA |
|
Peris et al, 2005c |
70/75 (93.3) |
NA |
|
Sterry et al, 2002b |
3x/week with occlusion: 20/23 (87) |
NA |
|
Vidal et al, 2004b |
3x and 5x/week: 4/4 (100) |
NA |
Notes:
a value for primary sBCC lesions (could not be verified). For sBCC (primary and non-primary)
complete response was observed in 75/88 (85.2%). Complete response was assessed 6
months post-treatment.
b six weeks post-treatment.
c time point of assessing complete response was not reported.
Patient response rates at 12 weeks post treatment for MAL-PDT ranged from 72% (T205)
to 90% (T304), and patient response rates at 12 weeks post treatment for imiquimod
dosed at five times per week ranged from 75% (Geisse et al, 2004) to 90% (Gollnick
et al, 2005). The patient response rates in the MAL-PDT trials/studies were results
at 3 months after the last treatment, where a proportion of patients underwent re-treatment.
Thus they do not solely represent recurrence rates following a single course of MAL-PDT
treatment (i.e. two treatments, 1 week apart).
The following table summarises the results for the outcomes of lesion response and
recurrence rates in all of the MAL-PDT and imiquimod trials/studies presented in the
re-submission. The results for these outcomes were not presented in the previous re-submission.
Results of lesion response and recurrence rates in all MAL-PDT and imiquimod trials/studies
presented in the re-submission
|
Trial/study |
Lesion response |
Recurrence rate |
||
|---|---|---|---|---|
|
MAL-PDT/ imiquimod |
Cryotherapy/ Placeboa |
MAL-PDT/ imiquimod |
Cryotherapy/ Placeboa |
|
|
MAL-PDT |
||||
|
T304 |
109/114 (96)* |
94/105 (90)* |
Patient |
Patient |
|
T310 |
84/92 (91)*,b |
NA |
Patient |
NA |
|
T205 |
42/49 (86)*,b |
NA |
Patient |
NA |
|
Soler et al, 2001 |
119/131 (91)b,i |
NA |
sBCC: 12/119 (9)i |
NA |
|
Surrenti et al, 2007 |
84/94 (89)b,j |
NA |
sBCC: 2/84 (2.4)k |
NA |
|
Caekelbergh et al, 2006 |
NR |
NA |
NR |
NA |
|
Imiquimod |
||||
|
Geisse et al, 2004 |
NR |
NA |
NR |
NA |
|
Gollnick et al, |
NR |
NA |
Patient: 10.4%l |
NA |
|
Shumack et al, |
NR |
NA |
NA |
NA |
|
Geisse et al, 2002 |
NR |
NR |
NR |
NR |
|
Marks et al, 2001 |
NR |
NA |
NR |
NA |
|
Peris et al, 2005 |
NR |
NA |
Patient: 2/70 (2.9)m |
NA |
|
Sterry et al, 2002 |
NR |
NA |
NR |
NA |
|
Vidal et al, 2004 |
NR |
NA |
Patient: 0/4 (0)n |
NA |
Notes:
Patient=patient recurrence rate, sBCC=sBCC recurrence rate, NR=not reported, NA-not
applicable
* at 3 months
a cryotherapy for MAL-PDT and placebo for imiquimod trials
b sBCC lesions
c at 24 months after the last treatment of patients in complete response 3 months
after the last treatment (21 month recurrence rate)
d at 60 months after the last treatment of patients in complete response 3 months
after the last treatment (57 month recurrence rate)
i after a follow-up of at 24-48, mean 35 months
j one month following two MAL-PDT sessions
k after a follow-up period of 6-18 months, mean 12 months
l The calculation is based on the ratio of the estimated proportion of subject who
remained clear by the initial complete response rate. The final recurrence rate is
1 – the results of the ratio (89.6% at 12 weeks)
m after a follow-up period of 12-34 months, mean 23 months
n after a 2 year follow-up
The results showed the lesion response rate in the MAL-PDT trials/studies ranged from
86% (T205) to 96% (T304). The patient recurrence rates reported in the MAL-PDT trials/studies
ranged from 16% (T310) to 33% (T304) at 12 months and between 28% (T310) and 42% (T304)
at 60 months (where reported), the patient recurrence rates reported for these MAL-PDT
trials/studies were results at 12 and 60 months after the last treatment, where a
proportion of patients underwent re-treatment thus, they do not solely represent recurrence
rates following a single course of MAL-PDT treatment (two treatments 1 week apart).
The patient recurrence rates reported for the imiquimod trials/studies ranged from
0% (Vidal et al, 2004) to 10.4% (Gollnick et al, 2005) (where reported). The PBAC
noted the comparison of the patient recurrence rates in the MAL-PDT and imiquimod
trials/studies was limited as the trials/studies differed when the lesion response
and recurrence rates were determined. Lesion recurrence rates in the MAL-PDT trials/studies
ranged from ranged from 2.4% (Surrenti et al, 2007) to 38% (T205), where reported.
The re-submission presented new toxicity data from the additional MAL-PDT and imiquimod
studies presented in the re-submission, where safety data were reported. The toxicity
data presented in the additional MAL-PDT and imiquimod trials/studies were consistent
with those reported in the studies presented in the previous re-submission.
9. Clinical Claim
The submission described MAL-PDT as non-inferior in terms of comparative effectiveness
and non-inferior in terms of comparative safety over imiquimod.
The PBAC noted that as with the previous re-submission, the evidence base from which
the MAL-PDT and imiquimod comparison is made was subject to significant bias.
The PBAC considered that the re-submission contained no new data which would cause
the Committee to alter its previous view that it lacked confidence that MAL-PDT is
no worse than imiquimod in terms of efficacy and safety.
10. Economic Analysis
The re-submission presented a cost minimisation analysis. The equi-effective dose
of MAL-PDT versus imiquimod was two sessions of MAL-PDT one week apart equalling 24
sachets of imiquimod. This was changed from the previous re-submission where one course
of MAL-PDT was claimed to be equivalent to 24 sachets of imiquimod in 70% of patients
and 30 sachets of imiquimod in 30% of patients.
The PBAC noted the appropriate number of imiquimod sachets to use in the cost-minimisation
analysis was a continuing area of economic uncertainty for the Committee. Although
the PBS allows up to 12 sachets of imiquimod with one repeat to be provided to a patient
for the treatment of each lesion, the clinicians present felt that most lesions would
be treated with less than the maximum number of sachets and that a repeat dispensing
would not always be required. The PBAC considered this uncertainty could be resolved
through an analysis of the Medicare Australia dispensing data for imiquimod.
11. Estimated PBS Usage and Financial Implications
The submission estimated likely number of patients was between 10,000 and 50,000 in Year 5 at a financial cost/year to the PBS of less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC agreed that the restriction wording proposed by the Restrictions Working
Group was appropriate, noting that the sponsor has accepted this wording in the pre-PBAC
response.
The PBAC considered that the re-submission contained no new data which would cause
the Committee to alter its previous view that it lacked confidence that MAL-PDT is
no worse than imiquimod in terms of efficacy and safety. Acceptance of the claim in
the pre-PBAC response that “MAL-PDT is non-inferior to imiquimod” continues to be
hampered by a lack of scientific rigour in the studies which form its evidentiary
base.
The Committee further considered that the data on recurrence rates show that MAL-PDT
has recurrence rates at 2 and 5 years which suggested recurrences was greater with
MAL-PDT than that associated with imiquimod.
A continuing area of economic uncertainty for the Committee was the appropriate number
of imiquimod sachets to use in the cost-minimisation analysis. Although the PBS allows
up to 12 sachets of imiquimod with 1 repeat to be provided to a patient for the treatment
of each lesion, the clinicians present felt that most lesions would be treated with
less than the maximum number of sachets and that a repeat dispensing would not always
be required. The PBAC considered this uncertainty could be resolved through an analysis
of the Medicare Australia dispensing data for imiquimod.
The PBAC also noted that there continues to be some dispute about which costs should
be included in the cost-minimisation analysis, with the sponsor alternately including
or excluding the same costs. The Committee confirmed that a cost-minimisation analysis
should consider costs to society and therefore that the exclusion of non-government
costs from the analysis in the pre-PBAC response was inappropriate.
The Committee therefore again rejected the application because of uncertain comparative
effectiveness and additionally because of problems with the cost-minimisation analysis.
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
With reference to the comparative effectiveness of Metvix-PDT therapy in the context of difficult to treat superficial basal cell carcinoma, the sponsor considers Metvix as a more appropriate topical treatment for superficial basal cell carcinomas in immunocompromised patients and in those patients who are unable to self medicate. The sponsor will consider the options available and refers readers to its website (www.treatskincancer.com or www.metvix.com) for further information.
