Regulatory Decision Summary for Taro-Calcipotriol / Betamethasone Gel

Betamethasone dipropionate is the compound generating the primary therapeutic effect of the proposed calcipotriol/betamethasone combination product. As for other topical products containing corticosteroids, the use of pharmacodynamic endpoints for assessing local exposure to betamethasone is necessary due to circulating levels that are below levels of detection.

In order to evaluate the bioequivalence of topical corticosteroids, the United States Food and Drug Administration (FDA) has developed guidelines for the use of a vasoconstrictor assay. The assay measures the ability of topically applied glucocorticoids to produce blanching in normal skin.

The Division of Biopharmaceutics Evaluation (DBE) considers that the methodology described in the FDA published guidance document entitled Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (1995), is an acceptable approach to be used in order to replace the conventional human pharmacokinetic in vivo studies in assessing the equivalence of two betamethasone topical products.

More specifically, in accordance with the aforementioned guidance document, data from the following two studies conducted in healthy adult volunteers should be provided:

1. Pilot Vasoconstrictor Study
   • Objective: Determination of the optimal dose-duration of the reference product (i.e., Median Effective Dose [ED₅₀]);

2. Pivotal Vasoconstrictor Study
   • Objective: Comparison of the biological activity (skin blanching) between the test and reference products;
   • Equivalence requirement in selected detectors: The 90% confidence interval for the skin blanching response ratio, defined as the ratio of the mean Area Under Curve (AUC) response resulting from the test product to the mean AUC response resulting from the reference product should be between 80% and 125%, inclusive.

The assessment is to be based on chromameter determinations of the vasoconstriction.

In addition to the above described vasoconstrictor studies, and in accordance with the approach described in the most recent United States FDA draft guidance document for generic betamethasone dipropionate/calcipotriene hydrate topical products (2011), a randomized, double blind, parallel, placebo-controlled in vivo study should be conducted in human male and female subjects with a clinical diagnosis of psoriasis vulgaris (plaque psoriasis).

The current submission included reports from the four following studies:

1. The pilot pharmacodynamic (PD) vasoconstrictor study number BTCG-1711-DD, involving 26 healthy subjects, was designed to determine the optimal dose-duration of the reference product for use in the pivotal phase.
2. The pivotal PD vasoconstrictor study BTCG-1711-BE, involving 106 healthy subjects, compared the biological activity of the Test gel (Taro-Calcipotriol/Betamethasone) with that of the CRP gel (Dovobet).
3. The comparative clinical endpoint study BTCG-1808 was conducted in subjects with a clinical diagnosis of body psoriasis using the CRP as a comparator. This study assessed the clinical efficacy after 8 weeks (56 days) of treatment using four clinical endpoints.
4. The comparative clinical endpoint study BTCS-1614 was conducted in subjects with a clinical diagnosis of scalp psoriasis using a reference product from the USA market. This study was submitted as supportive evidence for the proposed indicated treatment of scalp psoriasis.

The pilot and pivotal pharmacodynamic vasoconstrictor studies BTCG-1711-DD and BTCG-1711-BE were reviewed by DBE2. The evaluated data and results indicate that the Test product (Taro-Calcipotriol/Betamethasone Gel) meets the equivalence requirements versus the Canadian Reference Product (CRP) (Dovobet Gel) as per the applicable evaluation standards described in the FDA published guidance document entitled Topical Dermatologic Corticosteroids: In Vivo Bioequivalence (1995).

Data and results from Studies BTCG-1808 and BTCS-1614 were reviewed by the Reproductive and Urology Division (RUD) of Bureau of Metabolism, Oncology and Reproductive Sciences (BMORS). As indicated in a consultation report to DBE2, the evidence submitted in study BTCG-1808 supports the therapeutic equivalence and comparable safety profile between Taro’s product and the CRP for the topical treatment of mild to moderate plaque psoriasis vulgaris on the body. Furthermore, a cursory review of data and results from the supportive Study BTCS-1614 indicates therapeutic equivalence and comparable safety profile between Taro’s product and the reference product from United States market (Taclonex) for the topical treatment of scalp psoriasis.

Adequate characterisation data and comparative analysis were provided to support that the generic product and innovator product are essentially the same. Taro-Calcipotriol / Betamethasone Gel (50 mcg/g calcipotriol (as monohydrate) and 0.5 mg/g betamethasone (as dipropionate)) has the identical medicinal ingredients, dosage form, route of administration and conditions of use as those of the CRP.

The drug substances and drug product are manufactured in a consistent manner.

After evaluation of the data package submitted, Health Canada authorized the product.