Clindamycin phosphate with benzoyl peroxide, gel, 10 mg (base) - 50 mg per gm (1% – 5%), 25 gm, Duac® Once Daily Gel, March 2009
Public summary document for Clindamycin phosphate with benzoyl peroxide, gel, 10 mg (base) - 50 mg per gm (1% – 5%), 25 gm, Duac® Once Daily Gel, March 2009
Page last updated: 03 July 2009
Public Summary Document
Product: Clindamycin phosphate with benzoyl
peroxide, gel, 10 mg (base) - 50 mg per gm (1% – 5%), 25 gm,
Duac® Once Daily Gel
Sponsor: Stiefel Laboratories Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a Restricted benefit listing for clindamycin
phosphate 1% with benzoyl peroxide 5% gel for the treatment of
moderate acne vulgaris with inflammatory lesions in patients with
an inadequate response to a minimum of two over-the-counter
products.
2. Background
The PBAC has not previously considered this product.
3. Registration Status
Duac Once Daily Gel® was TGA registered on 30 January 2006 for
the topical treatment of comedo, papules and pustular acne
vulgaris.
4. Listing Requested and PBAC’s View
Restricted Benefit
Treatment of moderate acne vulgaris with inflammatory lesions in
patients with an inadequate response to a minimum of two
over-the-counter medications.
In the Pre-PBAC response, noting comment made during the
evaluation, the sponsor proposed the following restriction
wording:
Moderate acne vulgaris with a minimum of 20 inflammatory lesions
(papules or pustules) in a patient with an inadequate response to
at least two other topical therapies.
NOTE: Duration should not exceed 11 weeks.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
The availability of clindamycin 1% and benzoyl peroxide 5% gel
would provide a PBS-subsidised treatment for patients with moderate
acne vulgaris.
6. Comparator
The submission nominated no treatment (placebo) as the main
comparator as there are currently no treatments for moderate acne
listed on the PBS. The submission also nominated topical retinoids,
topical antibiotics and benzoyl peroxide as secondary
comparators.
Whether the product would remain as a third-line treatment if PBS
listed was a concern, with a potential for use earlier if available
as a subsidised treatment, and also in mild acne, given there are
no products specifically listed for this indication.
7. Clinical Trials
The submission presented:
- five direct randomised trials with four treatment arms: four
trials of clindamycin + benzoyl peroxide gel (i.e. Duac),
clindamycin alone, benzoyl peroxide alone, and placebo gel, and one
trial of clindamycin + benzoyl peroxide gel, clindamycin alone and
benzoyl peroxide alone, without a placebo arm;
- one direct randomised trial with two treatment arms, comparing
clindamycin plus benzoyl peroxide gel with the topical retinoid
adapalene (Langner 2008); and
- one supportive study of quality of life measures with the use of
clindamycin plus benzoyl peroxide gel in Korean patients in
Korea.
The trials published at the time of submission are detailed below:
| Trial ID/First Author | Protocol title/ Publication title | Citation |
| Direct randomised trial | ||
| Langner 2008 | A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide and adapalene in the treatment of mild to moderate facial acne vulgaris. | Brit J Derm 2008 158(1): 122-9 |
| Study 150 Lookingbill D.P. et al | Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: Combined results of two double-blind investigations | Journal of the American Academy of Dermatology 1997; 37(4): 590-595. |
8. Results of Trials
The pooled results of the percentage reduction in counts of
inflammatory and non-inflammatory lesions in the five direct
randomised trials with four treatment arms demonstrated that
treatment with Duac results in a statistically significant
reduction in both inflammatory and non-inflammatory lesion counts
at 11 weeks compared with once per day treatment with benzoyl
peroxide, clindamycin or placebo, though with wide confidence
intervals.
The pooled results of the physician assessed global improvement,
proportion of “good” or “excellent”
improvement in the same studies was increased with Duac treatment
compared with benzoyl peroxide (risk ratio 1.32 [95%CI 1.13,
1.56]), clindamycin (risk ratio 1.66 [95%CI 1.25, 2.20]) and
placebo (risk ratio 3.85 [95%CI 1.56, 9.45]).
The most common adverse event for Duac was local skin irritation
comparable with benzoyl peroxide alone.
The PBAC noted the TGA Resistance Risk Assessment report concerning
Duac was prepared for review by the Expert Advisory Group on
Antimicrobial Resistance. The report concluded that there was no
evidence that the combination product would make the emergence of
resistance in targeted or other bacteria more likely than topical
clindamycin alone, and that the combination of clindamycin and
benzoyl peroxide may make the emergence of clindamycin resistant
bacteria less likely. However, the report also recommended that a
maximum course of treatment with Duac should be 12 weeks, without
further continuation of clindamycin containing topical
therapies.
As with topical clindamycin, Duac has rarely been associated with
pseudomembranous colitis.
9. Clinical Claim
The submission claimed that Duac was superior to benzoyl peroxide,
clindamycin, placebo and adapalene in terms of reduction in
inflammatory and non-inflammatory lesions and global improvement in
acne vulgaris of the face, and equivalent to these treatments in
terms of safety and tolerance.
The PBAC agreed with the clinical claims that clindamycin with
benzoyl peroxide was more effective than benzoyl peroxide,
clindamycin, placebo and adapalene, and was equivalent to these
treatments in terms of safety and tolerance. It was noted that four
of the key trials included patients with mild acne.
10.Economic Analysis
A stepped economic evaluation was presented comparing the costs and
consequences of Duac compared with no treatment in patients with
moderate acne. The submission estimated the base case incremental
cost per QALY gained was less than $15,000.
The submission presented the results of a number of univariate
sensitivity analyses. The model was most sensitive to alternative
utilities for the responder and non-responder health states, with
the incremental cost per QALY gained less than $15,000 when
utilities from Chen, et al (2008) were used (assuming responders
achieve 50% acne clearance). The model was also sensitive to
including the proportion of responders in the ‘no
treatment’ arm from the meta-analysis of key trials (16.8%;
base case: 0%), and included the costs of GP visits to obtain
scripts for Duac. Combining these three analyses resulted in an
incremental cost per QALY gained in the range
$15,000-$45,000.
The PBAC noted the results of multivariate sensitivity analyses
conducted during the evaluation. These analyses demonstrated that
the model is sensitive to the utility assumptions, the assumption
of no responders in the placebo arm (rather than 16.8% as in the
meta-analysis) and the inclusion of GP costs associated with
clindamycin.
11. Estimated PBS Usage and Financial Implications
The financial cost per year to the PBS was estimated to be less
than $10 million in Year 5 of listing.
12. Recommendation and Reasons
The PBAC noted the amended restricted benefit listing sought, as
proposed in the Pre-PBAC Response, however, it considered a
definition of ‘moderate acne’ remained problematic, and
the requirement for the use of two prior topical preparations while
reasonable, would be impractical to implement. Further, that a Note
stating use per treatment was limited to 11 weeks would be of
limited value in a restricted benefit listing, and there was a high
potential for long-term use of the product. While the TGA approved
Product Information recommended that a course of treatment be
limited to a maximum duration of 11 weeks, the PBAC agreed that
patients would want to continue treatment after this time, if it is
effective.
Whether the product would remain as a third-line treatment if PBS
listed was a concern, with a potential for use earlier in the
treatment algorithm if available as a subsidised treatment, and
also in mild acne, given no products are specifically listed for
this indication.
The PBAC agreed with the clinical claims that clindamycin with
benzoyl peroxide is more effective than benzoyl peroxide,
clindamycin, placebo and adapalene, and is equivalent to these
treatments in terms of safety and tolerance. It was noted that four
of the key trials included patients with mild acne.
The PBAC noted that given survival benefit is not an issue in this
condition all the benefits of treatment are derived from an
improvement in quality of life (QOL). The Committee noted there
were several areas of uncertainty with the economic
modelling.
A key concern to the PBAC was is in relation to the translation of
the QOL outcomes observed in the trials to QALY weights and QALYs.
The QOL results were drawn from only one study (which included
patients with mild and moderate acne), as this was the only study
presented that included a QOL scale, the Dermatology Life Quality
Index (DLQI). The trial was carried out in a Korean population and
there were concerns about the generalisability of these QOL results
to the PBS population. The PBAC noted the Pre-Sub-Committee
response considered that the applicability of the DLQI results to
the Australian population was supported by the available evidence,
citing the results of two studies (Fernandez-Obregon et al. 2003
and Chen et al. 2008) which the sponsor regards as showing that
there are similar improvements in QOL and utility scores for Asian
compared to Caucasian patients. However, the PBAC noted that the
Chen et al. study compares groups of Asian-American and Caucasian
teenagers who both live in America where there was likely to be
greater cultural similarity than across Korean and Australian
populations. Thus the finding of similarity is not necessarily
generalisable. The PBAC considered that the applicability of the
results from the Korean study to the Australian population remains
uncertain, noting that there are well documented differences across
countries in QOL assessment and utility assessment with the same
instrument.
Another key issue was that the DLQI scores in acne were then
translated to EQ-5D utility scores with the use of a mapping
algorithm for psoriasis patients from Woolacott et al. (2006)
[EQ-5D utility score = 0.956 – [0.0248 x (DLQI total
score)]] to translate the DLQI scores to a utility score for
acne patients. The PBAC considered there are likely to be other
factors that affect the QOL in psoriasis patients compared to acne
patients that would not be captured by this mapping algorithm.
Further, the precision of the mapping algorithm was uncertain as
there is no information concerning the confidence interval around
the reported coefficients from the regression based mapping.
The PBAC noted the Pre-Sub-Committee response argued that in the
model the attributing of all the utility gain observed to
responders did not favour clindamycin with benzoyl peroxide,
however, the PBAC was not convinced as there were more responders
in the clindamycin with benzoyl peroxide arm. The PBAC agreed there
was uncertainty associated with the modelling assumption that the
utility gain for responders occurs for half of the first period of
treatment (6 weeks of 12) but for all subsequent treatment periods
and that the total utility gain is implicitly assumed to occur for
the whole of the “on treatment” period. This not only
assumes that utility gains from initial treatment are sustained in
subsequent treatments over a 12 month period but also implies a
greater utility gain in the later treatment periods than in the
first period.
Overall, the PBAC considered the approach to measuring utilities to
be highly uncertain and appeared to overestimate the utility gain
associated with treatment because of (1) use of a psoriasis-based
mapping algorithm (2) the assumptions in relation to non-responders
(3) the assumption that the Korean QOL results apply to Australian
population (4) the assumption that these results apply to moderate
to severe acne.
Other factors contributing to the economic uncertainty associated
with the requested listing were in relation to costs and the
assumptions relating to the proportion of responders in the placebo
arm and the extent of acne clearance in responders.
The PBAC considered the base case ICER of less than $ 15,000 per
QALY gained was sensitive to a number of assumptions, and the
multivariate sensitivity analyses conducted during the evaluation
produced values in the range $ 15,000 to $ 45,000. However, the
PBAC was advised that these may have been applied inappropriately.
The base case non-responder utility in this sensitivity analysis is
0.932, on the basis that this was the “own” health
state utility for Chen participants who had seen a GP for their
acne. The responder utility is 0.978 (assuming 100% acne clearance
in responders) – which corresponds to the
“clearance” utility for the whole Chen population. If
the value for the responder state is based on the whole Chen
population then it is also appropriate for the base
case/non-responder utility to be based on the same sample, that is
the “own” utility for the whole Chen population
(=0.961). The approach taken in the submission is to selectively
pick utilities from different populations at different time points,
which is not appropriate. Recalculating the ICER with this value
gives an ICER within the range of $45,000-$75,000 per QALY but
higher than when using the “responder” utility value.
When a similar adjustment is made to the sensitivity analyses that
use the Chen utilities assuming 50% acne clearance in responders,
the ICER falls in the range $75,000-$105,000 per QALY as opposed to
less than $15,000 per QALY. When the additional assumptions queried
by the PBAC are tested in sensitivity analyses these ICERs will
become higher.
Therefore, the PBAC agreed there is considerable uncertainty
surrounding the ICERs as a result of the approach to modelling QALY
gains, leading to an ICER that is highly uncertain and likely to be
much higher than the base case in the submission.
The Committee noted that no other drug had been recommended for PBS
listing for the treatment of moderate (or mild) acne vulgaris, and
in the absence of a clear definition of mild to moderate questioned
whether PBS subsidisation was appropriate at this time. If mild is
interpreted without qualification, the guidelines for submissions
to the PBAC state in Box 1.2 that low priority is given to a
listing for a drug for the treatment of clinically minor or trivial
conditions.
The PBAC also considered there was not a high clinical need for the
product, and was concerned that the wider availability and
potential for long term use may contribute to the increase in
community acquired MRSA resistance given the significant market for
the gel.
The PBAC rejected the application on the basis of unacceptably high
and uncertain cost effectiveness, uncertainty with its clinical
place and the potential for the development of antibiotic
resistance.
The PBAC noted that the submission meets the criteria for an
Independent Review.
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 has no comments.
