Regulatory Decision Summary for Clobivis

The purpose of this New Drug Submission (NDS) was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations for Clobivis (clobetasol propionate) ophthalmic suspension 0.05% filed by Apotex Inc. for the treatment of post-operative inflammation and pain following ocular surgery. Upon review the submitted data package, the recommended indication was for the treatment of post-operative inflammation and pain following cataract surgery.

The proposed indication was supported by data from two almost identically designed, multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase 3 studies (CPN 301 and CPN 302) conducted in patients ≥18 years old who were scheduled for unilateral, uncomplicated cataract extraction via phacoemulsification with posterior chamber intraocular lens implantation in one eye. Both Phase 3 studies evaluated the efficacy and safety of Clobivis (0.05%) 1 drop instilled twice daily (BID) in the study eye for 14 days following routine uncomplicated cataract surgery treatment, with the exception that study CPN-302 included a sub-study to assess corneal endothelial cell safety parameters at post operative day 85 (POD 85).

The study population had to have ≥10 cells in the anterior chamber after cataract surgery and no history of glaucoma, ocular hypertension, steroid-related intra ocular pressure (IOP) rise, corneal abrasion/ulceration, and had an IOP between <22 mm Hg and >5 mm Hg on Day 1 after surgery. In these two studies, one drop of Clobivis 0.05% or placebo was self-administered twice a day for 14 days, beginning on the day after surgery.

Efficacy was evaluated using slit-lamp biomicroscopy to assess anterior chamber cell (ACC) counts on a 5-point scale (0-4) and subject-reported ocular pain in the operated eye graded on a 5-point scale. The co-primary efficacy endpoints were the proportion of subjects with ACC Count = 0 (ACC Grade = 0) both at post operative day 8 (POD8) and post operative day 15 (POD15) and the proportion of subjects with Ocular Pain Grade = 0 both at post operative day (POD4) and POD15.

A total of 748 subjects were randomized in the two Phase III studies: 378 and 370 participants in studies CPN 301 (181 randomized to Clobivis and 197 to placebo) and CPN 302 (185 randomized to Clobivis and 185 to placebo), respectively. Most patients (73%) were ≥65 years of age, and 56% were females. The primary efficacy results of the proportion of subjects with complete resolution of ACC at day 8 maintained through day 15 post cataract surgery was significantly greater in Clobivis-treated patients compared to placebo-treated patients (26.5% vs. 5.1%; p<0.001) and (26.5% vs. 8.6%; p<0.001) (Intention-to-treat [ITT] population) for study CPN 301 and CPN 302 respectively. The second primary efficacy endpoint of no pain at day 4 post cataract surgery was also significantly greater in Clobivis-treated patients compared to placebo-treated patients (68.0% vs. 23.4%; p<0.0001) and (75.1%% vs.32.4%; p<0.0001) (ITT population) for study CPN 301 and CPN 302 respectively. Secondary efficacy endpoints were generally supportive of the primary endpoints

Overall, the efficacy results were consistent across the two pivotal studies regarding the primary and secondary endpoints. In both studies, treatment with Clobivis BID for 14 days after cataract surgery resulted in a statistically significantly greater proportion of subjects with complete clearance of ACC from POD8 and complete absence of ocular pain from POD4 maintained through POD15 compared with matching vehicle placebo.

The safety review was based on the integrated safety database in Clobivis patients across five clinical studies, including two pivotal trials. In total, there were 431 patients that were treated with Clobivis and 448 patients receiving Placebo. The patients in Phase 3 trials were treated for 14 days, a group of patients in Phase II study were treated for 21 days, while patients in Phase I trials were treated with one or two single drops of Clobivis separated by approximately 8-12 hours. In these studies, the most frequent treatment emergent adverse events (TEAEs) (≥1% in any treatment group) were inflammation (2.3%), corneal edema (2.1%), anterior chamber inflammation (1.9%), cystoid macular edema (1.6%), intraocular pressure elevation (IOP) (2.1%), photophobia (1.2%) and vitreous detachment (1.2%). The overall incidence of ocular TEAEs was lower in the Clobivis group (17.9%) compared with the Placebo group (21.0%). IOP increased was more frequent with Clobivis (2.1%, n = 9) compared to placebo (0.2%, n = 1) group. However, IOP increased is a well-known and common effect of ophthalmic corticosteroids, and these cases did not require study drug discontinuation. No deaths, no serious adverse events related to study drug, and no clinically significant laboratory parameter changes (including serum cortisol) were observed in these studies. No meaningful differences in slit lamp biomicroscopy or ophthalmoscopy findings were reported between groups. Withdrawals from study due to TEAEs were rare and unrelated to study drug. Overall, the safety profile of Clobivis in these studies is mostly in line with the expected safety profile of other corticosteroid eye drops. No safety concerns with respect to systemic effects of corticosteroids were identified as pharmacokinetic studies demonstrated minimal systemic concentration clobetasol propionate. Identified and potential safety risks are adequately labelled in the approved Product Monograph along with the risk mitigation measures.

A Risk Management Plan (RMP) for Clobivis was submitted by Apotex Inc. to Health Canada. Upon review, the RMP was considered to be acceptable.

There is substantial evidence to demonstrate the efficacy of Clobivis in the reduction of post-operative inflammation and pain within the study eye in adult patients following cataract surgery. Clobivis presents an acceptable and manageable safety profile in this study population. Therefore, based on the data submitted by the sponsor, the benefit-harm-uncertainty profile of Clobivis (Clobetasol Propionate) ophthalmic suspension 0.05%, is favourable for the treatment of post-operative inflammation and pain following cataract surgery when used under the conditions of use recommended in the approved Product Monograph.

Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Clobivis, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.