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Ingenol Mebutate (Picato): Topical Treatment of Non-hyperkeratotic, Non-hypertrophic Actinic Keratosis in Adults [Internet]

Ingenol Mebutate (Picato): Topical Treatment of Non-hyperkeratotic, Non-hypertrophic Actinic Keratosis in Adults [Internet]

Common Drug Review - Canadian Agency for Drugs and Technologies in Health

Version: February 2014

SUMMARY

Ingenol mebutate gel (Picato) is a topical cream that the manufacturer is requesting to use as a second-line treatment in patients with actinic keratosis (AK) who have failed or are intolerant to 5-fluorouracil (5-FU). Ingenol mebutate gel is available in two strengths – a 0.015% dose for lesions on the face and scalp and a 0.05% dose for lesions on the trunk and extremities. Both strengths cost $383.00 per treatment course. The manufacturer submitted a cost-minimization analysis against 5-FU in the trunk and extremity indication, and against 5-FU and imiquimod 5% in the face and scalp indication. No appropriate evidence of comparative effectiveness was presented.

CONCLUSIONS

The cost per course of treatment with ingenol mebutate ($383) is similar to that of imiquimod 5% depending on how it is dosed ($353 to $529), 2 These costs are based on a range of 12 weeks to 16 weeks treatment with imiquimod 5%. The low range of 12 weeks was provided by clinical expert advice where patients receive one 24-dose pack of imiquimod 5%, while the upper range is based on patients receiving a pack of 24 doses and a pack of 12 doses (total 36 doses) to cover 16 weeks of treatment; based on the pack size and treatment regimen specified in the imiquimod 5% Product Monograph. but considerably higher than that of 5-FU ($34). Whether ingenol mebutate will generate savings or incur additional costs if listed by public plans depends on how ingenol mebutate will be utilized. If ingenol mebutate is used only by AK patients who have failed 5-FU treatment, listing ingenol mebutate may generate modest savings when compared with imiquimod 5%. However, if ingenol mebutate is used as a first-line therapy for AK (as per the Health Canada indication), listing ingenol mebutate would result in substantially higher costs being incurred by public plans.

ISSUES FOR CONSIDERATION

Potential for use of ingenol mebutate as first-line therapy. Based on clinical experience, the Health Canada indication, and available clinical evidence, ingenol mebutate may be used as a first-line topical therapy. If ingenol mebutate is used as a first-line topical agent, this would incur substantially higher treatment costs for public plans than the current first-line topical agent (5-FU). The price of ingenol mebutate. Given the potential use of ingenol mebutate as a first-line treatment in clinical practice, a price reduction analysis was undertaken versus the current first-line therapy, 5-FU (Appendix 1: Price Reduction Analysis). This analysis indicates that a price reduction of more than 90% is likely required for ingenol mebutate to become cost-saving if used as a first-line therapy. Other issues. Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) rejected an application for ingenol mebutate to be listed on its Pharmaceutical Benefits Scheme (PBS) on the basis of uncertainty in the clinical claim and cost-effectiveness, and that “utilization is uncertain, and is likely to be high and substantially underestimated in the submission.” This decision and others are summarized in Appendix 2: Review of Other HTA Agency Reports.

INTRODUCTION

0.015% for lesions on the face and scalp 0.05% for lesions on the trunk or extremities.

INTERPRETATIONS AND KEY LIMITATIONS

Lack of data to support second-line therapy. In the clinical studies, only a small proportion of patients received ingenol mebutate after having received 5-FU. Although the results of a subgroup analysis for this population are generally similar to the overall patient population, the results appear to indicate that ingenol mebutate works better as a first-line topical agent. However, the population is small and thus the robustness of these results is uncertain. The majority of the clinical data are for use as a first-line treatment, in line with the Health Canada indication. No robust evidence that ingenol mebutate gel is equivalent to 5-FU and/or imiquimod 5%. As indicated in Appendix 7 of the clinical report, the systematic review by Gupta et al. (2012) does not adequately assess the indirect treatment comparison of ingenol mebutate gel 0.015% versus 5-FU or imiquimod 5% in patients with AK on the face or scalp; or ingenol mebutate gel 0.05% versus 5-FU in patients on the trunk or extremities. Although the systematic review met all assessing methodological quality of systematic reviews (AMSTAR) criteria and is considered to be of high methodological quality, it was limited by the heterogeneity and low methodological quality of the included studies. Model cycle time may not be appropriate. The manufacturer stated that clinical experts consulted indicated that patients would be reassessed between four and six months after treatment, but use a six-month cycle as opposed to a four-month cycle. The clinical expert consulted by the Common Drug Review (CDR) indicated that assessment at four months was more likely to be appropriate. During the two-year period, the use of a four-month cycle substantially increases the incremental cost of ingenol mebutate compared with 5-FU compared with using a six-month cycle. Therefore, the use of a six-month cycle by the manufacturer has likely underestimated the actual treatment costs. Adherence and persistence. The manufacturer’s analysis did not consider the potential for greater adherence and persistence rates with ingenol mebutate when compared with either comparator due to the substantially shorter treatment duration with ingenol mebutate. The benefits from the shorter treatment duration cannot be seen in the submitted analysis. The only available data related to persistence and adherence are from a patient survey from the UK, in which persistence and adherence rates for ingenol mebutate (~70%) were higher compared with 5-FU (45% to 52%). However, by not taking the improved adherence and persistence into account, the manufacturer may have underestimated the total cost of treatment with ingenol mebutate compared with the comparator treatments. Inappropriate pricing of imiquimod 5%. It would have been more appropriate to use prices from plans that participate within the CDR process as opposed to using Régie de l'assurance maladie du Québec (RAMQ) pricing in the cost comparison. The submission also presents the results using the cost of exactly 32 doses, although the manufacturer only supplies the imiquimod 5% in packs of 24 and 12. It is thus likely to have wastage (assuming all 32 doses are prescribed). This needed to be taken into account when determining the cost of this comparator, which may increase or decrease the cost of imiquimod 5%, depending on the prescribing habits of clinicians.

SUMMARY OF PHARMACOECONOMIC SUBMISSION

The manufacturer submitted a cost-minimization analysis (CMA), considering only the direct cost of drugs related to treatment of AK. The objective of the CMA was to compare the cost of ingenol mebutate compared with imiquimod 5% or 5-FU in patients who had previously failed or were intolerant to 5-FU. Four treatment sequences were assessed in the model for the two strengths and indications (Table 2).

OBJECTIVES AND METHODS

To perform a systematic review of the beneficial and harmful effects of ingenol mebutate once daily for the topical treatment of non-hyperkeratotic, non-hypertrophic AK for the face and scalp (0.015% gel, three-day treatment) and for the trunk and extremities (0.05% gel, two-day treatment) in adult patients.

INTRODUCTION

Actinic keratosis (AK) is a common, precancerous skin condition characterized by thickened, cornified, scaly lesions that develop as a result of chronic ultraviolet (UV) irradiation. Risk factors for AK include fair skin types (Fitzpatrick skin type I or II), older age, and a history of chronic sun exposure. Lesions are predominantly found on sun-exposed areas such as the face, bald scalp, ears, and forearms. Approximately 60% of people older than 40 years old with a history of UV exposure have at least one AK lesion. Since there is a lack of well-designed Canadian AK studies, the prevalence of AK in Canada in 2011 was estimated to be 4.4% using data from a German population-based study, affecting a total of 1.5 million people.

EXECUTIVE SUMMARY

Actinic keratosis (AK) is a precancerous skin condition that develops as a result of chronic ultraviolet (UV) exposure and was estimated to affect 1.5 million Canadians in 2011. AK is characterized by thickened, scaly lesions that are skin to reddish-brown in colour. The rate of progression from AK to squamous cell carcinoma (SCC) is estimated to be 0.025% to 20% per year for an individual lesion. The choice of treatment is guided by the clinical presentation of the condition, with lesion-directed therapies being appropriate for few and isolated lesions, and field-directed therapies being used for areas of skin with multiple lesions. Field-directed therapies include topical 5-fluorouracil (5-FU), imiquimod, and now ingenol mebutate. Ingenol mebutate is a diterpene ester purified from the Euphorbia peplus plant that induces cell death through cytotoxic and neutrophil-dependent inflammatory mechanisms. In Canada, ingenol mebutate is available as a 0.05% gel (once daily for two days, for trunk and extremities) or 0.015% gel (once daily for three days, for face and scalp), supplied in unit-dose tubes for topical application.

CDEC Final Recommendation

The Canadian Drug Expert Committee (CDEC) recommends that ingenol mebutate not be listed.

RESULTS

A total of four studies were identified from the literature for inclusion in the systematic review (Figure 1). The included studies are summarized in Table 5 and described in Section 3.2. A list of excluded studies is presented in APPENDIX 3: EXCLUDED STUDIES.

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