Adapalene with benzoyl peroxide, gel, 1 mg – 25 mg per g (0.1%-2.5%), 30 g, Epiduo®
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Product: Adapalene with benzoyl peroxide, gel, 1 mg – 25 mg per g (0.1%-2.5%), 30 g, Epiduo®
Sponsor: Galderma Australia Pty Ltd
Date of PBAC Consideration: November 2010
1. Purpose of Application
To request a restricted benefit listing for:
1) acute management of severe acne vulgaris as adjunctive therapy to an oral antibiotic; and
2) maintenance treatment of severe acne vulgaris.
This combination product had not previously been considered by the
3. Registration Status
Adapalene 0.1% with benzoyl peroxide 2.5% gel was TGA registered on
16 January 2009 for the cutaneous treatment of acne vulgaris on the
face, chest and back when comedones, papules and pustules are
present, and the condition has not responded to first line
4. Listing Requested and PBAC’s View
Acute treatment of severe acne vulgaris as adjunctive therapy to an oral antibiotic.
Maintenance treatment of severe acne vulgaris.
For PBAC’s view, see Recommendations and Reasons.
5. Clinical Place for the Proposed Therapy
It was proposed that adapalene with benzoyl peroxide
(adapalene-BPO) would provide a treatment option for severe acne
vulgaris which may be used before oral retinoid therapy.
The submission nominated placebo as the comparator.
For PBAC’s view, see Recommendation and Reasons.
7. Clinical Trials
The basis of the submission was two direct randomised comparative
trials in severe acne, ACCESS-1 and ACCESS-2. In ACCESS-1, patients
were randomised to 12-weeks treatment with adapalene-BPO or placebo
in addition to oral doxycycline therapy (100 mg per day). The first
280 patients in the ACCESS-1 trial showing at least a good level of
improvement after 12 weeks of therapy were eligible for inclusion
in the ACCESS-2 continuation phase trial, where adapalene-BPO
monotherapy was compared to placebo vehicle gel.
The submission also includes three supplementary randomised comparative trials in patients with moderate acne (Gollnick 2009, Stein Gold 2009, and Thiboutot 2007) and two supportive safety studies on photosensitivity and skin irritancy (Loesche 2008, Martin 1998).
The trials published at the time of the submission are detailed in the table below.
|Trial ID / First author||Protocol title / Publication title||Publication citation|
|ACCESS-1 Stein Gold, et al. 2010||Effective and safe combination therapy for severe acne vulgaris: A randomized vehicle-controlled, double-blind study of adapalene 0.1% - benzoyl peroxide 2.5% fixed combination gel with doxycycline hyclate.||Cutis 2010; 85: 94-104|
|Gollnick, et al. 2009||Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients.||British Journal of Dermatology 2009; 161: 1180-89|
|Stein Gold, et al. 2009||A North American Study of adapalene-benzoyl peroxide combination gel in the treatment of acne.||Cutis 2009; 84: 110-116|
|Thiboutot, et al. 2007||Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: Results of a multicenter, randomized double-blind, controlled study.||J Am Acad Dermatol 2007, 57: 791-99|
|Loesche, et al. 2007||Adapalene 0.1% and benzoyl peroxide 2.5% as a fixed-dose combination gel is as well tolerated as the individual components alone in terms of cumulative irritancy.||Eur J Dermatol 2007; 18(5): 524-6|
|Martin, et al. 1998||Chemical stability of adapalene and tretinoin when compared with benzoyl peroxide in the presence and in absence of visible light and ultraviolet radiation.||Brit J Dermatol 1998; 139 (Suppl 52): 8-11|
8. Results of Trials
The primary outcome in ACCESS-1 was the mean change in total acne
lesion count from baseline to week 12. The two primary outcomes for
ACCESS-2 were maintenance of success (i.e. proportion of patients
maintaining 50% of the ACCESS-1 improvement at week 24, as defined
by a decrease in total lesion count), and time-to-relapse (i.e.
failure to maintain 50% of the ACCESS-1 improvement in total lesion
The PBAC noted that there were statistically significantly larger reductions in total lesion counts in adapalene with benzoyl peroxide treated patients than placebo treated patients at week 12 in ACCESS-1 (59% versus 37%). Additionally, statistically significantly more patients achieved a “clear/almost clear” score by the Investigator Global Assessment of Severity (31.5% adapalene-BPO, 8.4% placebo): These results were used in the economic model.
More adapalene-BPO treated patients than placebo treated patients in ACCESS-1 had greater total lesion count reductions at weeks 2, 4 and 8; greater reductions in both inflammatory and non-inflammatory lesion counts; showed improvement based on Investigator Global Assessment – Improvement scores; reported greater satisfaction on the domains of the Treatment Satisfaction Questionnaire; and reported improvements in acne symptoms as measured by the Acne Quality of Life (QoL) scale.
For the primary endpoints in the ACCESS-2 trial, the PBAC noted that there was a statistically significantly higher proportion of adapalene-BPO treated patients maintaining treatment success compared to placebo treated patients at 24 weeks and a statistically significantly longer time-to-relapse in adapalene with benzoyl peroxide treated patients.
In addition, the PBAC noted that adapalene-BPO treated patients in ACCESS-2 reported statistically significantly smaller changes in total lesion counts (consistent with maintenance of benefit in those responding to initial treatment with adapalene-BPO plus antibiotic). The proportion of patients achieving “clear/almost clear” status was increased in adapalene-BPO treated patients and was decreased in placebo treated patients. Statistically significantly more adapalene-BPO treated patients reported improvement on each of the four domains of the Acne QoL and all but one of the domains of the Satisfaction with Treatment Questionnaire.
There were few differences in proportions of patients reporting adverse events (AEs) and treatment related AEs between adapalene-BPO and placebo treated patients in ACCESS-1, with slightly more dermatological AEs (3% vs. 1.3%) and treatment related dermatological AEs (1.7% vs. 0.4%) in adapalene-BPO treated patients. There were higher rates of all AEs, treatment related AEs, and dermatological AEs in patients receiving adapalene-BPO compared to placebo in ACCESS-2. Treatment related AE rates were generally low and no patients in ACCESS-2 reported adverse events leading to treatment discontinuation.
9. Clinical Claim
The submission claimed adapalene-BPO adjunctive therapy with oral
doxycycline therapy was superior in comparative effectiveness to
doxycycline alone for severe acne based on the 12-week results of
ACCESS-1. The submission extended the claim of superiority to
36-weeks based on the 24-week “continuation of clinical
benefit” shown in ACCESS-2. The submission described
adapalene-BPO as non-inferior in terms of comparative safety based
on no statistically significant differences in adverse event rates
between adapalene-BPO and placebo-treated patients in ACCESS-1 and
For PBAC’s view, see Recommendation and Reasons.
10. Economic Analysis
A stepped economic evaluation was presented. The model was a
cost-utility analysis based on the results of the direct randomised
trials, extrapolated to one-year, and transformed using a responder
analysis and applying utilities from Klassen (2000).
The PBAC noted that the model was highly sensitive to the estimate of treatment effect, the utility gain and use beyond the requested indication in moderate acne. The incremental cost-effectiveness ratio (ICER) estimated in the submission, which included isotretinoin as a treatment for severe acne, was less than $15,000 per quality adjusted life year gained (QALY) but increased to between $15,000 and $45,000/QALY when a potential error in the application of utilities was corrected.
The PBAC noted that univariate sensitivity analyses using the corrected ICER showed that by using the lower bound of the 95% CI for the odds ratio, and a smaller utility gain, the ICERs increased to between $45,000 and $75,000/QALY. The ICER increased substantially within this range if use in moderate acne was considered.
For PBAC’s view, see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year estimated in the submission
was between 10,000 and 50,000 in Year 5.
The cost per year to the PBS was estimated in the submission to be less than $10 million in Year 5.
The PBAC considered there was potential for use beyond the requested restriction in moderate acne.
12. Recommendation and Reasons
The PBAC recommended the listing of adapalene with benzoyl peroxide
on the PBS with a Restricted Benefit listing for acute treatment,
in combination with an oral antibiotic, and maintenance treatment
of severe acne vulgaris on the basis of an acceptable
cost-effectiveness ratio compared with placebo.
The PBAC accepted that placebo was the appropriate comparator in both acute and maintenance settings. However, the PBAC noted that the definition of severe acne is subjective, and includes both physical and social contexts.
The PBAC considered that the 12-week results of the ACCESS-1 trial presented in the submission support the claim of superior comparative effectiveness of adapalene with benzoyl peroxide adjunctive therapy with doxycycline over doxycycline. The PBAC considered that the results of the ACCESS-2 trial, which compared adapalene plus benzoyl peroxide monotherapy with placebo, generally support the maintenance of benefit of treatment with adapalene with benzoyl peroxide in patients who have achieved an initial response with adapalene with benzoyl peroxide as adjunctive therapy to oral antibiotics.
There were statistically significantly larger reductions in total lesion counts (the primary endpoint) in adapalene with benzoyl peroxide treated patients than placebo treated patients at week 12 in ACCESS-1 (59% versus 37%). The PBAC noted that the dose of doxycycline used the ACCESS-1 trial was 100 mg and that this was consistent with the advice from the clinician during the sponsor’s hearing that higher doses (100 mg) of doxycycline or minocycline are usually indicated for treatment of severe acne.
For the primary endpoints in the ACCESS-2 trial, there was a statistically significantly higher proportion of adapalene with benzoyl peroxide treated patients maintaining treatment success compared to placebo treated patients at 24 weeks and a statistically significantly longer time-to-relapse in adapalene with benzoyl peroxide treated patients.
A stepped economic evaluation was presented using a cost-utility analysis. The PBAC noted that the model was highly sensitive to the estimate of treatment effect, the utility gain and use beyond the requested indication in moderate acne. The ICER estimated in the submission, which included isotretinoin as a treatment for severe acne, was less than $15,000/Quality Adjusted Life Year (QALY) but increased to between $15,000 and $45,000/QALY when an error in the application of utilities was corrected.
The results of the univariate sensitivity analyses using the corrected ICER increased the ICER to between $45,000 and $75,000/QALY using the lower bound of the 95% CI for the odds ratio and using a smaller utility gain. The PBAC considered that there was uncertainty surrounding the base-case ICER. The ICER increased substantially from the base case estimate if use in moderate acne was considered.
ADAPALENE with BENZOYL PEROXIDE, gel, 1 mg – 25 mg per g (0.1% - 2.5%), 30 g
Restriction: Restricted Benefit
Acute treatment, in combination with an oral antibiotic, of severe acne vulgaris.
Maximum quantity: 1
Restricted BenefitMaintenance treatment of severe acne vulgaris.
Continuing Therapy Onlys: For prescribing by nurse practitioners as continuing therapy only, where the treatment of, and prescribing of medicine for, a patient has been initiated by a medical practitioner. Further information can be found in the Explanatory Notes for Nurse Practitioners.
Maximum quantity: 1
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 thanks the PBAC and looks forward to the PBS listing for EPIDUO.